Substituted Spirocyclic Piperidine Derivatives as Histamine-3 (H3) Receptor Ligands

ABSTRACT

The present invention provides compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     their use as H 3  antagonists/inverse agonists, processes for their preparation, and pharmaceuticals compositions thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/US2009/032195, filed Jan. 28, 2009, which claims priority to U.S.Provisional Application Ser. No. 61/062,909, filed Jan. 30, 2008. Thedisclosures of the aforementioned applications are incorporated hereinby reference in their entireties for all purposes.

TECHNICAL FIELD

The present invention is related to substituted spirocyclic piperidinederivatives, their use as H₃ antagonists/inverse agonists, processes fortheir preparation, and pharmaceuticals compositions thereof.

BACKGROUND

Publications cited throughout this disclosure are incorporated in theirentirety herein by reference.

Histamine is a well established modulator of neuronal activity. At leastfour subtypes of histamine receptors have been reported in theliterature—H₁, H₂, H₃, H₄. The histamine H₃ receptors play a key role inneurotransmission in the central nervous system. The H₃ receptor wasdiscovered in 1983 originally on histamine-containing neurons where itwas shown to function presynaptically, regulating the release andsynthesis of the biogenic amine histamine (Arrang et al, 1983) now awell established neurotransmitter. H₃ receptors are predominatelyexpressed in the brain, localizing to the cerebral cortex, amygdala,hippocampus, striatum, thalamus and hypothalamus. H₃ receptors are alsolocalized presynaptically on histaminergic nerve terminals and act asinhibitory autoreceptors (Alguacil and Perez-Garcia, 2003; Passani etal, 2004; Leurs at al, 2005; Celanire et al, 2005; Witkin and Nelson,2004). When these receptors are activated by histamine, histaminerelease is inhibited. H₃ receptors can also be found in the periphery(skin, lung, cardiovascular system, intestine, GI tract, etc). H₃receptors are also involved in presynaptic regulation of the release ofacetylcholine, dopamine, GABA, glutamate and serotonin (seeRepka-Ramirez, 2003; Chazot and Hann, 2001; Leurs et al, 1998). The H₃receptor demonstrates a high degree of constitutive or spontaneousactivity (e.g., receptor is active in the absence of agoniststimulation) in vitro and in vivo, thus, ligands to the receptor candisplay, agonist, neutral antagonist or inverse agonist effects.

The location and function of histaminergic neurons in the CNS suggeststhat compounds interacting with the H₃ receptor may have utility in anumber of therapeutic applications including narcolepsy or sleep/wakedisorders, feeding behavior, eating disorders, obesity, cognition,arousal, memory, mood disorders, mood attention alteration, attentiondeficit hyperactivity disorder (ADHD), Alzheimer's disease/dementia,schizophrenia, pain, stress, migraine, motion sickness, depression,psychiatric disorders and epilepsy (Leurs et al, 2005; Witkin andNelson, 2004, Hancock and Fox 2004; Esbenshade et al. 2006). An H₃antagonist/inverse agonist could be important for gastrointestinaldisorders, respiratory disorders such as asthma, inflammation, andmyocardial infarction.

Ohtake et al. (US 2006/0178375 A1) disclosed compounds that reportedlyexhibit histamine receptor H₃ antagonist or inverse agonist activity andmay be useful for the treatment or prevention of obesity, diabetes,hormonal secretion abnormality, or sleep disorders.

Celanire et al. (WO 2006/103057 A1 and WO 2006/103045) have disclosedcompounds comprising an oxazoline or thiazoline moiety, processes forpreparing them, their pharmaceutical compositions and their uses as H₃ligands.

Bertrand et al. (WO 2006/117609 A2) disclosed novel histamine H₃receptor ligands, processes for their preparation, and their therapeuticapplications.

Schwartz et al. (WO 2006/103546 A2) disclosed certain methods oftreatment for Parkinson's disease, obstructive sleep apnea, narcolepsy,dementia with Lewy bodies, and/or vascular dementia using non-imidazolealkylamine derivatives that are antagonists of the H₃ receptors ofhistamine.

Apodaca et al. (EP 1 311 482 B1) disclosed certain non-imidazolearyloxypiperidines as H₃ receptor ligands, their synthesis, and theiruse for the treatment of disorders and conditions mediated by thehistamine receptor.

Xu et al. disclosed certain 6-substitutedphenyl-4,5-dihydro-3(2H)-pyridazinones, their synthesis, and rabbitplatelet aggregation inhibitory activity induced by ADP in vitro.

Barker et al. (US 2006/0217375) discloses spiro[benzodioxane] compoundsas active antagonists of the orexin-1 receptor and potentially useful inthe prophylaxis and treatment of orexin-1 receptor related disorders andorexin-2 receptor related disorders.

Thus, there is a need for novel classes of compounds that interact withthe H₃ receptor.

SUMMARY

The present invention is directed to compounds of Formula (I):

and the stereoisomeric forms, mixtures of stereoisomeric forms, andpharmaceutically acceptable salt forms thereof,

-   wherein:-   R¹ is H, C₁-C₄ alkyl, or C₃-C₈ cycloalkyl;-   W is —CH₂—, —CH₂CH₂—, or —CH₂—O—;-   k is 0, 1, or 2; m is 0, 1, or 2; and the sum of m and k is 1, 2, or    3;-   Y²═Y³ is —C(X)═CH— or —CH═C(X)—;-   X is R², —OR², —(C₁-C₃ alkyl)-R², —O—(C₁-C₃ alkyl)-R², —NHR²,    —NHC(═O)R², or —NHC(═O)NHR²; wherein said C₁-C₃ alkyl is optionally    substituted with —OH or C₁-C₄ alkoxy;-   R² is

-   A is F, Cl, or Br;-   R³ is H, F, or C₁-C₄ alkyl;-   R⁴ is H, F, or C₁-C₄ alkyl;-   R^(4A) is H, F, Cl, Br, or C₁-C₄ alkyl;-   R⁵ is H, F, or C₁-C₄ alkyl;-   R^(5A) is H, F, Cl, Br, C₁-C₄ alkyl or phenyl;-   alternatively, R⁴ and R⁵, together with the carbon atoms to which    they are attached, may form a fused C₃-C₆ cycloalkyl ring optionally    substituted with 1, 2, or 3 R¹⁴;-   alternatively, R^(4A) and R^(5A), together with the carbon atoms to    which they are attached, may form    -   a fused phenyl ring optionally substituted with 1, 2, or 3 R¹⁴;    -   a C₃-C₆ cycloalkyl ring optionally substituted with 1, 2 or 3        R¹⁴;    -   a 5 to 6 membered fused heteroaryl ring system containing one,        two, or three heteroatoms selected from N, O, and S, wherein        said heteroaryl ring system is optionally substituted with 1, 2,        or 3 R¹⁴; or    -   a 5 to 6 membered fused heterocycloalkyl ring system containing        one, two, or three heteroatoms selected from N, O, S, SO, and        SO₂, wherein said heterocycloalkyl ring system is optionally        substituted with 1, 2, or 3 R¹⁴;-   R⁶ is H, F, or C₁-C₄ alkyl;-   R⁷ is H, F, Cl, Br, or C₁-C₄ alkyl;-   R⁸ is H, —C(═O)R²⁷, —CO₂R²⁷, C₁-C₆ alkyl optionally substituted by    1-3 R²⁰;    -   C₃-C₈ cycloalkyl optionally substituted by 1-3 R^(20A);    -   C₆-C₁₀ aryl optionally substituted by 1-3 R^(20A);    -   C₇-C₁₅ arylalkyl optionally substituted by 1-3 R^(20A); or    -   a 5 to 10 membered heteroaryl ring system containing one, two,        or three heteroatoms selected from N, O, and S, wherein said        heteroaryl ring system is optionally substituted with 1-3        R^(20A);-   R⁹, at each occurrence, is independently F, Cl, Br, C₁-C₄ alkyl, or    C₁-C₄ alkoxy;-   R¹⁰ is F, Cl, Br, C₁-C₃ alkyl, or C₁-C₃ alkoxy;-   R¹⁴ at each occurrence is independently F, Cl, Br, I, —OR²¹, —OR²²,    —NR²³R²⁴, —NHOH, —NO₂, —CN, —CF₃, (═O), —C(═O)R²¹, —CO₂R²¹,    —OC(═O)R²¹, —C(═O)NR²³R²⁴, —NR²⁷C(═O)R²¹, —NR²⁷C(═O)OR²¹,    —OC(═O)NR²³R²⁴, —NR²⁷C(═S)R²¹, —SR²¹, —S(O)R²¹, or —S(O)₂R²¹; C₁-C₆    alkyl optionally substituted with OR²⁶; C₂-C₆ alkenyl, or C₂-C₆    alkynyl;-   R²⁰ at each occurrence is independently F, Cl, Br, I, —OR²¹, —OR²²,    —NR²³R²⁴, —NHOH, —NO₂, —CN, —CF₃, (═O), —C(═O)R²¹, —CO₂R²¹,    —OC(═O)R²¹, —C(═O)NR²³R²⁴, —NR²⁷C(═O)R²¹, —NR²⁷C(O)OR²¹,    —OC(═O)NR²³R²⁴, —NR²⁷C(═S)R²¹, —SR²¹, —S(O)R²¹, or —S(O)₂R²¹; C₁-C₆    alkyl optionally substituted with OR²⁶; C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₇ cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl    group, or 5- or 6-membered heteroaryl group;-   R^(20A) at each occurrence is independently F, Cl, Br, I, —OR²¹,    —OR²², —NR²³R²⁴, —NHOH, —NO₂, —CN, —CF₃, (═O), —C(═O)R²¹, —CO₂R²¹,    —OC(═O)R²¹, —C(═O)NR²³R²⁴, —NR²⁷C(═O)R²¹, —NR²⁷C(═O)OR²¹,    —OC(═O)NR²³R²⁴, —NR²⁷C(═S)R²¹, —SR²¹, —S(O)R²¹, or —S(O)₂R²¹; C₁-C₆    alkyl optionally substituted with OR²⁶; C₂-C₆ alkenyl, or C₂-C₆    alkynyl;-   R²¹ at each occurrence is independently H, C₁-C₆ alkyl, C₆-C₁₀ aryl,    or C₇-C₁₅ arylalkyl;-   R²² at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;-   R²³ and R²⁴ at each occurrence is independently selected from H,    C₁-C₆ alkyl, and C₆-C₁₀ aryl;-   alternatively, R²³ and R²⁴, together with the nitrogen atom to which    they are attached, form a 3 to 7 membered heterocycloalkyl ring    system containing one, two, or three heteroatoms selected from N, O,    and S, wherein said heterocycloalkyl ring system is optionally    substituted with ═O;-   R²⁶ is H or C₁-C₆ alkyl;-   R²⁷ is H or C₁-C₆ alkyl;-   n is 0, 1, 2, or 3; and-   z is 0, 1, 2, 3, 4, 5, or 6.

The present invention is also directed to methods of making compounds ofFormula (I), as well as methods of their pharmaceutical use.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

In preferred embodiments, the present invention provides compounds ofFormula (I):

or a stereoisomeric form, mixtures of stereoisomeric forms, orpharmaceutically acceptable salt forms thereof,

-   wherein:-   R¹ is H, C₁-C₄ alkyl, or C₃-C₅ cycloalkyl;-   W is —CH₂—, —CH₂CH₂—, or —CH₂—O—;-   k is 0, 1, or 2; m is 0, 1, or 2; and the sum of m and k is 1, 2, or    3;-   Y²═Y³ is —C(X)═CH— or —CH═C(X)—;-   X is R², —OR², —(C₁-C₃ alkyl)-R², —O—(C₁-C₃ alkyl)-R², —NHR²,    —NHC(═O)R², or —NHC(═O)NHR²; wherein said C₁-C₃ alkyl is optionally    substituted with —OH or C₁-C₄ alkoxy;-   R² is

-   A is F, Cl, or Br;-   R³ is H, F, or C₁-C₄ alkyl;-   R⁴ is H, F, or C₁-C₄ alkyl;-   R^(4A) is H, F, Cl, Br, or C₁-C₄ alkyl;-   R⁵ is H, F, or C₁-C₄ alkyl;-   R^(5A) is H, F, Cl, Br, C₁-C₄ alkyl or phenyl;-   alternatively, R⁴ and R⁵, together with the carbon atoms to which    they are attached, may form a fused C₃-C₆ cycloalkyl ring optionally    substituted with, 1, 2, or 3 R¹⁴;-   alternatively, R^(4A) and R^(5A), together with the carbon atoms to    which they are attached, may form    -   a fused phenyl ring optionally substituted with 1, 2, or 3 R¹⁴;    -   a C₃-C₆ cycloalkyl ring optionally substituted with 1, 2 or 3        R¹⁴;    -   a 5 to 6 membered fused heteroaryl ring system containing one,        two, or three heteroatoms selected from N, O, and S, wherein        said heteroaryl ring system is optionally substituted with 1, 2,        or 3 R¹⁴; or    -   a 5 to 6 membered fused heterocycloalkyl ring system containing        one, two, or three heteroatoms selected from N, O, S, SO, and        SO₂, wherein said heterocycloalkyl ring system is optionally        substituted with 1, 2, or 3 R¹⁴;-   R⁶ is H, F, or C₁-C₄ alkyl;-   R⁷ is H, F, Cl, Br, or C₁-C₄ alkyl;-   R⁸ is H, —C(═O)R²⁷, —CO₂R²⁷, C₁-C₆ alkyl optionally substituted by    1-3 R²⁰;    -   C₃-C₈ cycloalkyl optionally substituted by 1-3 R^(20A);    -   C₆-C₁₀ aryl optionally substituted by 1-3 R^(20A);    -   C₇-C₁₅ arylalkyl optionally substituted by 1-3 R^(20A); or    -   a 5 to 10 membered heteroaryl ring system containing one, two,        or three heteroatoms selected from N, O, and S, wherein said        heteroaryl ring system is optionally substituted with 1-3        R^(20A);-   R⁹, at each occurrence, is independently F, Cl, Br, C₁-C₄ alkyl, or    C₁-C₄ alkoxy;-   R¹⁰ is F, Cl, Br, C₁-C₃ alkyl, or C₁-C₃ alkoxy;-   R¹⁴ at each occurrence is independently F, Cl, Br, I, —OR²¹, —OR²²,    —NR²³R²⁴, —NHOH, —NO₂, —CN, —CF₃, (═O), —C(═O)R²¹, —CO₂R²¹,    —OC(═O)R²¹, —C(═O)NR²³R²⁴, —NR²⁷C(═O)R²¹, —NR²⁷C(═O)OR²¹,    —OC(═O)NR²³R²⁴, —NR²⁷C(═S)R²¹, —SR²¹, —S(O)R²¹, or —S(O)₂R²¹; C₁-C₆    alkyl optionally substituted with OR²⁶; C₂-C₆ alkenyl, or C₂-C₆    alkynyl;-   R²⁰ at each occurrence is independently F, Cl, Br, I, —OR²¹, —OR²²,    —NR²³R²⁴, —NHOH, —NO₂, —CN, —CF₃, (═O), —C(═O)R²¹, —CO₂R²¹,    —OC(═O)R²¹, —C(═O)NR²³R²⁴, —NR²⁷C(═O)R²¹, —NR²⁷C(═O)OR²¹,    —OC(═O)NR²³R²⁴, —NR²⁷C(═S)R²¹, —SR²¹, —S(O)R²¹, or —S(O)₂R²¹; C₁-C₆    alkyl optionally substituted with OR²⁶; C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₇ cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl    group, or 5- or 6-membered heteroaryl group;-   R^(20A) at each occurrence is independently F, Cl, Br, I, —OR²¹,    —OR²², —NR²³R²⁴, —NHOH, —NO₂, —CN, —CF₃, (═O), —C(═O)R²¹, —CO₂R²¹,    —OC(═O)R²¹, —C(═O)NR²³R²⁴, —NR²⁷C(═O)R²¹, —NR²⁷C(═O)OR²¹,    —OC(═O)NR²³R²⁴, —NR²⁷C(═S)R²¹, —SR²¹, —S(O)R²¹, or —S(O)₂R²¹; C₁-C₆    alkyl optionally substituted with OR²⁶; C₂-C₆ alkenyl, or C₂-C₆    alkynyl;-   R²¹ at each occurrence is independently H, C₁-C₆ alkyl, C₆-C₁₀ aryl,    or C₇-C₁₅ arylalkyl;-   R²² at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;-   R²³ and R²⁴ at each occurrence is independently selected from H,    C₁-C₆ alkyl, and C₆-C₁₀ aryl;-   alternatively, R²³ and R²⁴, together with the nitrogen atom to which    they are attached, form a 3 to 7 membered heterocycloalkyl ring    system containing one, two, or three heteroatoms selected from N, O,    and S, wherein said heterocycloalkyl ring system is optionally    substituted with ═O;-   R²⁶ is H or C₁-C₆ alkyl;-   R²⁷ is H or C₁-C₆ alkyl;-   n is 0, 1, 2, or 3; and-   z is 0, 1, 2, 3, 4, 5, or 6.

In preferred embodiments, the present invention provides novel compoundsof Formula

and stereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salt forms thereof, wherein:

-   R¹ is H, C₁-C₄ alkyl, or C₃-C₈ cycloalkyl;-   W is —CH₂—, —CH₂CH₂—, or —CH₂—O—;-   k is 0, 1, or 2; m is 0, 1, or 2; and the sum of m and k is 1, 2, or    3;-   Y²═Y³ is —C(X)═CH— or —CH═C(X)—;-   X is R², —OR², —(C₁-C₃ alkyl)-R², —O—(C₁-C₃ alkyl)-R², —NHR²,    —NHC(═O)R², or —NHC(═O)NHR²;-   R² is

-   R³ is H, F, or C₁-C₄ alkyl;-   R⁴ is H, F, or C₁-C₄ alkyl;-   R^(4A) is H, F, Cl, Br, or C₁-C₄ alkyl;-   R⁵ is H, F, or C₁-C₄ alkyl;-   R^(5A) is H, F, Cl, Br, or C₁-C₄ alkyl;-   alternatively, R⁴ and R⁵, together with the carbon atoms to which    they are attached, may form a fused C₃-C₆ cycloalkyl ring optionally    substituted with 1-3 R¹⁴;-   alternatively, R^(4A) and R^(5A), together with the carbon atoms to    which they are attached, may form    -   a fused phenyl ring optionally substituted with 1-3 R¹⁴;    -   C₃-C₆ cycloalkyl ring optionally substituted with 1-3 R¹⁴;    -   a 5 to 6 membered fused heteroaryl ring system containing one,        two, or three heteroatoms selected from N, O, and S, wherein        said heteroaryl ring system is optionally substituted with 1-3        R¹⁴; or    -   5 to 6 membered fused heterocycloalkyl ring system containing        one, two, or three heteroatoms selected from N, O, S, SO, and        SO₂, wherein said heterocycloalkyl ring system is optionally        substituted with 1-3 R¹⁴;-   R⁶ is H, F, or C₁-C₄ alkyl;-   R⁷ is H, F, Cl, Br, or C₁-C₄ alkyl;-   R⁸ is H, —C(═O)R²⁷, —CO₂R²⁷, C₁-C₆ alkyl optionally substituted by    1-3 R²⁰;    -   C₃-C₈ cycloalkyl optionally substituted by 1-3 R^(20A);    -   C₆-C₁₀ aryl optionally substituted by 1-3 R^(20A);    -   C₇-C₁₅ arylalkyl optionally substituted by 1-3 R^(20A); and    -   a 5 to 10 membered heteroaryl ring system containing one, two,        or three heteroatoms selected from N, O, and S, wherein said        heteroaryl ring system is optionally substituted with 1-3        R^(20A);-   R⁹, at each occurrence, is independently, F, Cl, Br, C₁-C₄ alkyl, or    C₁-C₄ alkoxy;-   R¹⁰ is F, Cl, C₁-C₃ alkyl, or C₁-C₃ alkoxy;-   R¹⁴ at each occurrence is independently, H, F, Cl, Br, I, —OR²¹,    —OR²², —NR²³R²⁴, —NHOH, —NO₂, —CN, —CF₃, (═O), —C(═O)R²¹, —CO₂R²¹,    —OC(═O)R²¹, —C(═O)NR²³R²⁴, —NR²⁷C(═O)R²¹, —NR²⁷C(═O)OR²¹,    —OC(═O)NR²³R²⁴, —NR²⁷C(═S)R²¹, —SR²¹, —S(O)R²¹, or —S(O)₂R²¹; C₁-C₆    alkyl optionally substituted with OR²⁶; C₂-C₆ alkenyl, or C₂-C₆    alkynyl;-   R²⁰ at each occurrence is independently, H, F, Cl, Br, I, —OR²¹,    OR²², —NR²³R²⁴, —NHOH, —NO₂, —CN, —CF₃, (═O), —C(═O)R²¹, —CO₂R²¹,    —OC(═O)R²¹, —C(═O)NR²³R²⁴, —NR²⁷C(═O)R²¹, —NR²⁷C(═O)OR²¹,    —OC(═O)NR²³R²⁴, —NR²⁷C(═S)R²¹, —SR²¹, —S(O)R²¹, or —S(O)₂R²¹; C₁-C₆    alkyl optionally substituted with OR²⁶; C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₇ cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl    group, or 5- or 6-membered heteroaryl group;-   R^(20A) at each occurrence is independently, H, F, Cl, Br, I, —OR²¹,    —OR²², —NR²³R²⁴, —NHOH, —NO₂, —CN, —CF₃, (═O), —C(═O)R²¹, —CO₂R²¹,    —OC(═O)R²¹, —C(═O)NR²³R²⁴, —NR²⁷C(═O)R²¹, —NR²⁷C(═O)OR²¹,    —OC(═O)NR²³R²⁴, —NR²⁷C(═S)R²¹, —SR²¹, —S(O)R²¹, or —S(O)₂R²¹; C₁-C₆    alkyl optionally substituted with OR²⁶; C₂-C₆ alkenyl, or C₂-C₆    alkynyl;-   R²¹ at each occurrence is independently H, C₁-C₆ alkyl, C₆-C₁₀ aryl,    or C₇-C₁₅ arylalkyl;-   R²² at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;-   R²³ and R²⁴ at each occurrence is independently selected from H,    C₁-C₆ alkyl, and C₆-C₁₀ aryl;-   alternatively, R²³ and R²⁴, together with the nitrogen atom to which    they are attached, form a 3 to 7 membered heterocycloalkyl ring    system containing one, two, or three heteroatoms selected from N, O,    and S, wherein said heterocycloalkyl ring system is optionally    substituted with ═O;-   R²⁶ is H or C₁-C₆ alkyl;-   R²⁷ is H or C₁-C₆ alkyl; and-   n is 0, 1, 2, or 3.

In preferred embodiments, the present invention provides compoundswherein R¹ is C₃-C₈ cycloalkyl.

In preferred embodiments, the present invention provides compoundswherein R¹ is cyclobutyl or cyclopentyl.

In preferred embodiments, the present invention provides compoundswherein W is —CH₂— or —CH₂—CH₂—.

In preferred embodiments, the present invention provides compoundswherein R² is

In preferred embodiments, the present invention provides compoundswherein R⁴ and R⁵, together with the carbon atoms to which they areattached, form a fused cyclopropyl or cyclobutyl ring.

In preferred embodiments, the present invention provides compoundswherein R^(4A) and R^(5A), together with the carbon atoms to which theyare attached, form a fused phenyl, thienyl, pyrrolyl, oxazolyl,pyridinyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring.

Preferred embodiments of the present invention include those wherein kis 1. Other embodiments include those wherein m is 1. Still otherembodiments include those wherein the sum of m and k is 2.

Also preferred within the present invention are those compounds whereinY²═Y³ is —C(X)═CH—. Also preferred are those compounds wherein X is R².In other preferred compounds of the invention, X is —OR².

In some embodiments of the present invention, R⁸ is H. In otherembodiments, R⁸ is C₁-C₆ alkyl optionally substituted by 1-3 R²⁰. Inother embodiments, R⁸ is C₁-C₆ alkyl.

In certain preferred embodiments, R⁹ is C₁-C₄ alkyl.

In some embodiments of the invention, n is 0. In other embodiments, itis preferred that n is 1. In other embodiments, z is preferably 0.

In a preferred embodiment, the present invention provides compounds ofFormula (II):

and stereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salt forms thereof, wherein:

-   R¹ is C₃-C₅ cycloalkyl;-   W is —CH₂— or —CH₂—CH₂—;-   X is R², —OR², or —NHR²;-   R² is

-   R³ is H or C₁-C₄ alkyl;-   R⁴ is H or C₁-C₄ alkyl;-   R^(4A) is H or C₁-C₄ alkyl;-   R⁵ is H or C₁-C₄ alkyl;-   R^(5A) is H or C₁-C₄ alkyl;-   alternatively, R⁴ and R⁵, together with the carbon atoms to which    they are attached, may form a fused C₃-C₆ cycloalkyl ring optionally    substituted with 1-3 R¹⁴;-   alternatively, R^(4A) and R^(5A), together with the carbon atoms to    which they are attached, may form    -   a fused phenyl ring optionally substituted with 1-3 R¹⁴;    -   C₃-C₆ cycloalkyl ring optionally substituted with 1-3 R¹⁴;    -   a 5 to 6 membered fused heteroaryl ring system containing one,        two, or three heteroatoms selected from N, O, and S, wherein        said heteroaryl ring system is optionally substituted with 1-3        R¹⁴; or    -   5 to 6 membered fused heterocycloalkyl ring system containing        one, two, or three heteroatoms selected from N, O, S, SO, and        SO₂, wherein said heterocycloalkyl ring system is optionally        substituted with 1-3 R¹⁴;-   R⁶ is H or C₁-C₄ alkyl;-   R⁷ is H or C₁-C₄ alkyl;-   R⁸ is H, —C(═O)R²⁷, —CO₂R²⁷, C₁-C₆ alkyl optionally substituted by    1-3 R²⁰;    -   C₃-C₈ cycloalkyl optionally substituted by 1-3 R^(20A);    -   C₆-C₁₀ aryl optionally substituted by 1-3 R^(20A);    -   C₇-C₁₅ arylalkyl optionally substituted by 1-3 R^(20A); and    -   a 5 to 10 membered heteroaryl ring system containing one, two,        or three heteroatoms selected from N, O, and S, wherein said        heteroaryl ring system is optionally substituted with 1-3        R^(20A);-   R⁹, at each occurrence, is independently, F, Cl, Br, C₁-C₄ alkyl, or    C₁-C₄ alkoxy;-   R¹⁰ is F, Cl, C₁-C₃ alkyl, or C₁-C₃ alkoxy;-   R¹⁴ at each occurrence is independently, H, F, Cl, Br, I, —OR²¹,    —OR²², —NR²³R²⁴, —NHOH, —NO₂, —CN, —CF₃, (═O), —C(═O)R²¹,    —C(═O)NR²³R²⁴, —NR²⁴C(═O)R²¹, —NR²⁷C(═O)OR²¹, —OC(═O)NR²³R²⁴,    —NR²⁷C(═S)R²¹, SR²¹, —S(O)R²¹, or —S(O)₂R²¹; C₁-C₆ alkyl optionally    substituted with OR²⁶; C₂-C₆ alkenyl, or C₂-C₆ alkynyl;-   R²⁰ at each occurrence is independently, H, F, Cl, Br, I, —OR²¹,    —OR²², —NR²³R²⁴, —NHOH, —NO₂, —CN, —CF₃, (═O), —C(═O)R²¹, —CO₂R²¹,    —OC(═O)R²¹, —C(═O)NR²³R²⁴, —NR²⁷C(═O)R²¹, —NR²⁷C(═O)OR²¹,    —OC(═O)NR²³R²⁴, —NR²⁷C(═S)R²¹, —SR²¹, —S(O)R²¹, or —S(O)₂R²¹; C₁-C₆    alkyl optionally substituted with OR²⁶; C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₇ cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl    group, or 5- or 6-membered heteroaryl group;-   R^(20A) at each occurrence is independently, H, F, Cl, Br, I, —OR²¹,    —OR²², —NR²³R²⁴, —NHOH, —NO₂, —CN, —CF₃, (═O), —C(═O)R²¹, —CO₂R²¹,    —OC(═O)R²¹, —C(═O)NR²³R²⁴, —NR²⁷C(═O)R²¹, —NR²⁷C(═O)OR²¹,    —OC(═O)NR²³R²⁴, —NR²⁷C(═S)R²¹, —SR²¹, —S(O)R²¹, or —S(O)₂R²¹; C₁-C₆    alkyl optionally substituted with OR²⁶; C₂-C₆ alkenyl, or C₂-C₆    alkynyl;-   R²¹ at each occurrence is independently H, C₁-C₆ alkyl, C₆-C₁₀ aryl,    or C₇-C₁₅ arylalkyl;-   R²² at each occurrence is independently the residue of an amino acid    after the hydroxyl group of the carboxyl group is removed;-   R²³ and R²⁴ at each occurrence is independently selected from H,    C₁-C₆ alkyl, and C₆-C₁₀ aryl;-   alternatively, R²³ and R²⁴, together with the nitrogen atom to which    they are attached, form a 3 to 7 membered heterocycloalkyl ring    system containing one, two, or three heteroatoms selected from N, O,    and S, wherein said heterocycloalkyl ring system is optionally    substituted with ═O;-   R²⁶ is H or C₁-C₆ alkyl;-   R²⁷ is H or C₁-C₆ alkyl; and-   n is 0, 1, 2, or 3.

In preferred embodiments, the present invention provides compoundswherein R¹ is cyclobutyl or cyclopentyl.

In preferred embodiments, the present invention provides compoundswherein R² is

In preferred embodiments, the present invention provides compoundswherein R⁴ and R⁵, together with the carbon atoms to which they areattached, form a fused cyclopropyl or cyclobutyl ring.

In preferred embodiments, the present invention provides compoundswherein R^(4A) and R^(5A), together with the carbon atoms to which theyare attached, form a fused phenyl, thienyl, pyrrolyl, oxazolyl,pyridinyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring.

In preferred embodiments, the present invention provides compoundswherein R⁸ is H.

In preferred embodiments, the present invention provides compounds ofFormula (III):

and stereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salt forms thereof, wherein:

-   R¹ is C₃-C₆ cycloalkyl;-   W is —CH₂— or —CH₂—CH₂—;-   R² is

-   R³ is H, methyl, or ethyl;-   R⁴ is H, methyl, or ethyl;-   R^(4A) is H, methyl, or ethyl;-   R⁵ is H, methyl, or ethyl;-   R^(5A) is H, methyl, or ethyl;-   alternatively, R⁴ and R⁵, together with the carbon atoms to which    they are attached, may form a fused C₃-C₆ cycloalkyl ring;-   alternatively, R^(4A) and R^(5A), together with the carbon atoms to    which they are attached, may form    -   a fused phenyl ring;    -   C₃-C₆ cycloalkyl ring;    -   a 5 to 6 membered fused heteroaryl ring system containing one,        two, or three heteroatoms selected from N, O, and S; or    -   5 to 6 membered fused heterocycloalkyl ring system containing        one, two, or three heteroatoms selected from N, O, S, SO, and        SO₂;-   R⁶ is H, methyl, or ethyl;-   R⁷ is H, methyl, or ethyl;-   R⁹, at each occurrence, is independently, F, Cl, methyl, ethyl,    methoxy, or ethoxy;-   R¹⁰ is F, Cl, methyl, ethyl, methoxy, or ethoxy; and-   n is 0, 1, or 2.

In a preferred embodiment, the present invention provides compounds ofFormula (III):

and stereoisomeric forms, mixtures of stereoisomeric forms orpharmaceutically acceptable salt forms thereof, wherein:

-   R¹ is cyclobutyl or cyclopentyl;-   W is —CH₂— or —CH₂—CH₂—;-   R² is

-   R³ is H, methyl, or ethyl;-   R⁴ is H, methyl, or ethyl;-   R^(4A) is H, methyl, or ethyl;-   R⁵ is H, methyl, or ethyl;-   R^(5A) is H, methyl, or ethyl;-   alternatively, R⁴ and R⁵, together with the carbon atoms to which    they are attached, may form a fused cyclopropyl, cyclobutyl, or    cyclopentyl ring;-   alternatively, R^(4A) and R^(5A), together with the carbon atoms to    which they are attached, may form a fused phenyl, thienyl, pyrrolyl,    oxazolyl, pyridinyl, cyclopropyl, cyclobutyl, cyclopentyl, or    cyclohexyl ring;-   R⁶ is H, methyl, or ethyl;-   R⁷ is H, methyl, or ethyl;-   R⁹, at each occurrence, is independently, F, Cl, methyl, ethyl,    methoxy, or ethoxy;-   R¹⁰ is F, Cl, methyl, ethyl, methoxy, or ethoxy; and-   n is 0, 1, or 2.

In a preferred embodiment, the present invention provides compoundswherein R² is

In another embodiment, the present invention provides pharmaceuticalcompositions comprising a compound according to the present inventionand one or more pharmaceutically acceptable excipients.

In a further embodiment the present invention provides for a method fortreating a disorder selected from the group consisting of narcolepsy orsleep/wake disorders, feeding behavior disorders, eating disorders,obesity, cognition disorders, arousal disorders, memory disorders, mooddisorders, mood attention alteration, attention deficit hyperactivitydisorder (ADHD), Alzheimer's disease/dementia, schizophrenia, pain,stress, migraine, motion sickness, depression, psychiatric disorders,epilepsy, gastrointestinal disorders, respiratory disorders,inflammation, and myocardial infarction comprising administering to asubject in need of such treatment a therapeutically effective amount ofa compound of the present invention. In a preferred embodiment thepresent invention provides for a method of treating narcolepsy orsleep/wake disorders. In a preferred embodiment the present inventionprovides for a method of treating attention deficit hyperactivitydisorder. In a preferred embodiment the present invention provides for amethod of treating cognition disorders.

In another embodiment the present invention provides for use of thecompounds of the present invention for use in therapy.

In a further embodiment the present invention provides for use of thecompounds of the present invention in the manufacture of a medicamentfor treating a disorder selected from the group consisting of narcolepsyor sleep/wake disorders, feeding behavior disorder, eating disorders,obesity, cognition disorders, arousal disorders, memory disorders, mooddisorders, mood attention alteration, attention deficit hyperactivitydisorder (ADHD), Alzheimer's disease/dementia, schizophrenia, pain,stress, migraine, motion sickness, depression, psychiatric disorders,epilepsy, gastrointestinal disorders, respiratory disorders,inflammation, and myocardial infarction comprising administering to asubject in need of such treatment a therapeutically effective amount ofa compound of the present invention.

DEFINITIONS

In the formulas described and claimed herein, it is intended that whenany symbol appears more than once in a particular formula orsubstituent, its meaning in each instance is independent of the other.

The following terms and expressions have the indicated meanings.

As used herein, the term “about” refers to a range of values from ±10%of a specified value. For example, the phrase “about 50” includes ±10%of 50, or from 45 to 55. The phrase “from about 10 to 100” includes ±10%of 10 and ±10% of 100, or from 9 to 110.

As used herein, a range of values in the form “x-y” or “x to y”, or “xthrough y”, include integers x, y, and the integers therebetween. Forexample, the phrases “1-6”, or “1 to 6” or “1 through 6” are intended toinclude the integers 1, 2, 3, 4, 5, and 6. Preferred embodiments includeeach individual integer in the range, as well as any subcombination ofintegers. For example, preferred integers for “1-6” can include 1, 2, 3,4, 5, 6, 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 2-6, etc.

As used herein “stable compound” or “stable structure” refers to acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and preferably capable offormulation into an efficacious therapeutic agent. The present inventionis directed only to stable compounds.

As used herein, “substituted” refers to any one or more hydrogen atomson the indicated atom is replaced with a selected group referred toherein as a “substituent,” provided that the substituted atom's valencyis not exceeded, and that the substitution results in a stable compound.

Examples of preferred substitutents are —OH, alkyl, cycloalkyl, alkoxy,halogen, haloalkyl, aryl, heteroaryl, and heterocyclyl.

As used herein, the term “alkyl” refers to a straight-chain, or branchedalkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl,neopentyl, 1-ethylpropyl, 3-methylpentyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, hexyl, octyl, etc. The alkyl moiety ofalkyl-containing groups has the same meaning as alkyl defined above. Adesignation such as “C₁-C₆ alkyl” refers to straight-chain, or branchedalkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl,neopentyl, 1-ethylpropyl, 3-methylpentyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, hexyl, etc. Lower alkyl groups, which are preferred,are alkyl groups as defined above which contain 1 to 4 carbons. Adesignation such as “C₁-C₄ alkyl” refers to an alkyl radical containingfrom 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, and tert-butyl. A designation such as “C₁-C₃alkyl” refers to an alkyl radical containing from 1 to 3 carbon atoms,such as methyl, ethyl, propyl, and isopropyl. Alkyl groups can besubstituted or unsubstituted. Preferred substitutents include —OH andalkoxy.

As used herein, the term “alkenyl” refers to a straight chain, orbranched hydrocarbon chains of 2 to 8 carbon atoms having at least onecarbon-carbon double bond. A designation “C₂-C₈ alkenyl” refers to analkenyl radical containing from 2 to 8 carbon atoms. Examples of alkenylgroups include ethenyl, propenyl, isopropenyl, 2,4-pentadienyl, etc.Alkenyl groups can be substituted or unsubstituted

As used herein, the term “alkynyl” refers to a straight chain, orbranched hydrocarbon chains of 2 to 8 carbon atoms having at least onecarbon-carbon triple bond. A designation “C₂-C₈ alkynyl” refers to analkynyl radical containing from 2 to 8 carbon atoms. Examples includeethynyl, propynyl, isopropynyl, 3,5-hexadiynyl, etc. Alkynyl groups canbe substituted or unsubstituted.

As used herein, the term “C₁-C₄ haloalkyl” refers to an “alkyl” group asdefined herein substituted by one or more halogen atoms to form a stablecompound. Examples of haloalkyl, include but are not limited to, —CF₃,—CHF₂, —CH₂F and CF₂CF₃.

As used herein, the term “C₁-C₄ alkoxy” refers to an “alkyl” group asdefined herein bonded to and oxygen atom. Alkoxy groups can besubstituted or unsubstituted.

As used herein, the term “halo” refers to an F, Cl, Br, and I. Preferredhalo substituents are F and Cl.

As used herein, the term “arylalkyl” or “aralkyl” refers to an alkylgroup that is substituted with an aryl group. A designation “C₂-C_(is)arylalkyl” refers to an arylalkyl radical containing from 7 to 15 carbonatoms. Examples of arylalkyl groups include, but are not limited to,benzyl, phenethyl, diphenylmethyl, diphenylethyl, naphthylmethyl, etc.preferably benzyl. Arylalkyl groups can be substituted or unsubstituted.

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated mono- or bicyclic alkyl ring system containing 3 to 10 carbonatoms. Certain embodiments contain 3 to 6 carbon atoms, and otherembodiments contain 5 or 6 carbon atoms. A designation such as “C₅-C₇cycloalkyl” refers to a cycloalkyl radical containing from 5 to 7 ringcarbon atoms. Examples of cycloalkyl groups include such groups ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, pinenyl, and adamantanyl. Cycloalkyl groups can besubstituted or unsubstituted

As used herein, the term “aryl” refers to a substituted orunsubstituted, mono- or bicyclic hydrocarbon aromatic ring system having6 to 12 ring carbon atoms. Examples include phenyl and naphthyl.Preferred aryl groups include unsubstituted or substituted phenyl andnaphthyl groups. Aryl groups can be substituted or unsubstituted

As used herein, the terms “heterocycle”, “heterocyclic” or“heterocyclyl” refer to a substituted or unsubstituted carbocyclic groupin which one or more ring carbon atoms are replaced by at least onehetero atom such as —O—, —N—, or —S—. Certain embodiments include 3 to 6membered rings, and other embodiments include 5 or 6 membered rings. Thenitrogen and sulfur heteroatoms may be optionally oxidized, and thenitrogen may be optionally substituted in non-aromatic rings.Heterocycles are intended to include heteroaryl and heterocycloalkylgroups. Heterocyclic groups can be substituted or unsubstituted.

As used herein, the term “heteroaryl” refers to an aromatic group orring system containing 5 to 10 ring carbon atoms in which one or morering carbon atoms are replaced by at least one hetero atom such as O, N,or S. Certain embodiments include 5 or 6 membered rings. Examples ofheteroaryl groups include pyrrolyl, furanyl, thienyl, pyrazolyl,imidazolyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxathiolyl,oxadiazolyl, triazolyl, oxatriazolyl, furazanyl, tetrazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, picolinyl,imidazopyridinyl, indolyl, isoindolyl, indazolyl, benzofuranyl,isobenzofuranyl, purinyl, quinazolinyl, quinolyl, isoquinolyl,benzoimidazolyl, benzothiazolyl, benzothiophenyl, thianaphthenyl,benzoxazolyl, benzooxadiazolyl, benzisoxazolyl, cinnolinyl,phthalazinyl, naphthyridinyl, and quinoxalinyl. Heteroaryl groups can besubstituted or unsubstituted.

As used herein, the term “heterocycloalkyl” refers to a cycloalkyl groupin which one or more ring carbon atoms are replaced by at least onehetero atom such as O, N, S, SO, and SO₂. Certain embodiments include 3to 6 membered rings, and other embodiments include 5 or 6 memberedrings. Examples of heterocycloalkyl groups include azetidinyl,pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, oxazolidinyl,pirazolidinyl, pirazolinyl, pyrazalinyl, piperidyl, piperazinyl,hexahydropyrimidinyl, morpholinyl, thiomorpholinyl, dihydrobenzofuranyl,tetrahydrofuranyl, tetrahydropyranyl, dihydro-oxazolyl, dithiolyl,oxathiolyl, dioxazolyl, oxathiazolyl, pyranyl, oxazinyl, oxathiazinyl,and oxadiazinyl. Included within the definition of “heterocycloalkyl”are fused ring systems, including, for example, ring systems in which anaromatic ring is fused to a heterocycloalkyl ring. Examples of suchfused ring systems include, for example, phthalamide, phthalicanhydride, indoline, isoindoline, tetrahydroisoquinoline, chroman,isochroman, chromene, and isochromene. Heterocycloalkyl groups can besubstituted or unsubstituted.

As used herein, the term “pyridazin-3-one moiety” refers to a 6 to 10membered heterocycloalkyl ring system containing a pyridazin-3-one groupand optionally a second fused ring. The second fused ring, if present,is optionally a substituted or unsubstituted phenyl ring, a substitutedor unsubstituted C₃-C₆ cycloalkyl ring, a substituted or unsubstituted 5to 6 membered fused heteroaryl ring system containing one, two, or threeheteroatoms selected from N, O, and S, or a a substituted orunsubstituted 5 to 6 membered fused heterocycloalkyl ring systemcontaining one, two, or three heteroatoms selected from N, O, and S.Examples of a second fused ring include, but are not limited to, phenyl,thienyl, pyrrolyl, oxazolyl, pyridinyl, cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

As used herein, the term “arylalkyl” refers to an alkyl group that issubstituted with an aryl group. Examples of arylalkyl groups include,but are not limited to, benzyl, bromobenzyl, phenethyl, benzhydryl,diphenylmethyl, triphenylmethyl, diphenylethyl, naphthylmethyl, etc.Arylalkyl groups can be substituted or unsubstituted.

As used herein, the term “amino acid” refers to a group containing bothan amino group and a carboxyl group. Embodiments of amino acids includeα-amino, β-amino, γ-amino acids. The α-amino acids have a generalformula HOOC—CH(side chain)-NH₂. The amino acids can be in their D, L orracemic configurations. Amino acids include naturally-occurring andnon-naturally occurring moieties. The naturally-occurring amino acidsinclude the standard 20 α-amino acids found in proteins, such asglycine, serine, tyrosine, proline, histidine, glutamine, etc.Naturally-occurring amino acids can also include non-α-amino acids (suchas β-alanine, γ-aminobutyric acid, homocysteine, etc.), rare amino acids(such as 4-hydroxyproline, 5-hydroxylysine, 3-methylhistidine, etc.) andnon-protein amino acids (such as citrulline, ornithine, canavanine,etc.). Non-naturally occurring amino acids are well-known in the art,and include analogs of natural amino acids. See Lehninger, A. L.Biochemistry, 2^(nd) ed.; Worth Publishers: New York, 1975; 71-77, thedisclosure of which is incorporated herein by reference. Non-naturallyoccurring amino acids also include α-amino acids wherein the side chainsare replaced with synthetic derivatives. In certain embodiments,substituent groups for the compounds of the present invention includethe residue of an amino acid after removal of the hydroxyl moiety of thecarboxyl group thereof; i.e., groups of formula —C(═O)CH(sidechain)-NH₂. Representative side chains of naturally occurring andnon-naturally occurring α-amino acids include are shown below in TableA.

TABLE A H CH₃— HO—CH₂— C₆H₅—CH₂— HO—C₆H₄—CH₂—

HS—CH₂— HO₂C—CH(NH₂)—CH₂—S—S—CH₂— CH₃—CH₂— CH₃—S—CH₂—CH₂—CH₃—CH₂—S—CH₂—CH₂— HO—CH₂—CH₂— C₅H₉— C₆H₁₁— C₆H₁₁—CH₂— CH₃—CH(OH)—HO₂C—CH₂—NHC(═O)—CH₂— HO₂C—CH₂— HO₂C—CH₂—CH₂— NH₂C(═O)—CH₂—NH₂C(═O)—CH₂—CH₂— (CH₃)₂—CH— (CH₃)₂—CH—CH₂— CH₃—CH₂—CH₂—H₂N—CH₂—CH₂—CH₂— H₂N—C(═NH)—NH—CH₂—CH₂—CH₂— H₂N—C(═O)—NH—CH₂—CH₂—CH₂—CH₃—CH₂—CH(CH₃)— CH₃—CH₂—CH₂—CH₂— H₂N—CH₂—CH₂—CH₂—CH₂—

As used herein, the term “subject” refers to a warm blooded animal suchas a mammal, preferably a human, or a human child, which is afflictedwith, or has the potential to be afflicted with, one or more diseasesand conditions described herein.

As used herein, a “therapeutically effective amount” refers to an amountof a compound of the present invention effective to prevent or treat thesymptoms of particular disorder. Such disorders include, but are notlimited to, those pathological and neurological disorders associatedwith the aberrant activity of the receptors described herein, whereinthe treatment or prevention comprises inhibiting, inducing, or enhancingthe activity thereof by contacting the receptor with a compound of thepresent invention.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for contact withthe tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem complicationscommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable compounds, materials, compositions, and/or dosage formsshould be on the Generally Recognized as Safe (GRAS) list.

As used herein, the term “unit dose” refers to a single dose which iscapable of being administered to a patient, and which can be readilyhandled and packaged, remaining as a physically and chemically stableunit dose comprising either the active compound itself, or as apharmaceutically acceptable composition, as described hereinafter.

All other terms used in the description of the present invention havetheir meanings as is well known in the art.

In another aspect, the present invention is directed to pharmaceuticallyacceptable salts of the compounds described above. As used herein,“pharmaceutically acceptable salts” includes salts of compounds of thepresent invention derived from the combination of such compounds withnon-toxic acid or base addition salts.

Acid addition salts include inorganic acids such as hydrochloric,hydrobromic, hydroiodic, sulfuric, nitric and phosphoric acid, as wellas organic acids such as acetic, citric, propionic, tartaric, glutamic,salicylic, oxalic, methanesulfonic, para-toluenesulfonic, succinic, andbenzoic acid, and related inorganic and organic acids.

Base addition salts include those derived from inorganic bases such asammonium and alkali and alkaline earth metal hydroxides, carbonates,bicarbonates, and the like, as well as salts derived from basic organicamines such as aliphatic and aromatic amines, aliphatic diamines,hydroxy alkamines, and the like. Such bases useful in preparing thesalts of this invention thus include ammonium hydroxide, potassiumcarbonate, sodium bicarbonate, calcium hydroxide, methylamine,diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and thelike.

In addition to pharmaceutically-acceptable salts, other salts areincluded in the invention. They may serve as intermediates in thepurification of the compounds, in the preparation of other salts, or inthe identification and characterization of the compounds orintermediates.

The pharmaceutically acceptable salts of compounds of the presentinvention can also exist as various solvates, such as with water,methanol, ethanol, dimethylformamide, ethyl acetate and the like.Mixtures of such solvates can also be prepared. The source of suchsolvate can be from the solvent of crystallization, inherent in thesolvent of preparation or crystallization, or adventitious to suchsolvent. Such solvates are within the scope of the present invention.

The present invention also encompasses the pharmaceutically acceptableprodrugs of the compounds disclosed herein. As used herein, “prodrug” isintended to include any compounds which are converted by metabolicprocesses within the body of a subject to an active agent that has aformula within the scope of the present invention. Since prodrugs areknown to enhance numerous desirable qualities of pharmaceuticals (e.g.,solubility, bioavailability, manufacturing, etc.) the compounds of thepresent invention may be delivered in prodrug form. Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in Prodrugs, Sloane, K. B., Ed.;Marcel Dekker: New York, 1992, incorporated by reference herein in itsentirety

It is recognized that compounds of the present invention may exist invarious stereoisomeric forms. As such, the compounds of the presentinvention include both diastereomers and enantiomers. The compounds arenormally prepared as racemates and can conveniently be used as such, butindividual enantiomers can be isolated or synthesized by conventionaltechniques if so desired. Such racemates and individual enantiomers andmixtures thereof form part of the present invention.

It is well known in the art how to prepare and isolate such opticallyactive forms. Specific stereoisomers can be prepared by stereospecificsynthesis using enantiomerically pure or enantiomerically enrichedstarting materials. The specific stereoisomers of either startingmaterials or products can be resolved and recovered by techniques knownin the art, such as resolution of racemic forms, normal, reverse-phase,and chiral chromatography, recrystallization, enzymatic resolution, orfractional recrystallization of addition salts formed by reagents usedfor that purpose. Useful methods of resolving and recovering specificstereoisomers described in Eliel, E. L.; Wilen, S. H. Stereochemistry ofOrganic Compounds; Wiley: New York, 1994, and Jacques, J, et al.Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981, eachincorporated by reference herein in their entireties.

It is further recognized that functional groups present on the compoundsof Formula I may contain protecting groups. For example, the amino acidside chain substituents of the compounds of Formula I can be substitutedwith protecting groups such as benzyloxycarbonyl or t-butoxycarbonylgroups. Protecting groups are known per se as chemical functional groupsthat can be selectively appended to and removed from functionalities,such as hydroxyl groups and carboxyl groups. These groups are present ina chemical compound to render such functionality inert to chemicalreaction conditions to which the compound is exposed. Any of a varietyof protecting groups may be employed with the present invention.Preferred groups for protecting lactams include silyl groups such ast-butyldimethylsilyl (“TBDMS”), dimethoxybenzhydryl (“DMB”), acyl,benzyl (“Bn”), and methoxybenzyl groups. Preferred groups for protectinghydroxy groups include TBS, acyl, benzyl, benzyloxycarbonyl (“CBZ”),t-butyloxycarbonyl (“Boc”), and methoxymethyl. Many other standardprotecting groups employed by one skilled in the art can be found inGreene, T. W. and Wuts, P. G. M., “Protective Groups in OrganicSynthesis” 2d. Ed., Wiley & Sons, 1991.

Synthesis

The compounds of the present invention may be prepared in a number ofmethods well known to those skilled in the art, including, but notlimited to those described below, or through modifications of thesemethods by applying standard techniques known to those skilled in theart of organic synthesis. All processes disclosed in association withthe present invention are contemplated to be practiced on any scale,including milligram, gram, multigram, kilogram, multikilogram orcommercial industrial scale.

The compounds of the present invention may be prepared in a number ofmethods well known to those skilled in the art, including, but notlimited to those described below, or through modifications of thesemethods by applying standard techniques known to those skilled in theart of organic synthesis. All processes disclosed in association withthe present invention are contemplated to be practiced on any scale,including milligram, gram, multigram, kilogram, multikilogram orcommercial industrial scale.

Condensation of an 4-oxobutyric acid or ester intermediate of generalstructure A, or a derivative there of, with hydrazine or an R⁸N-substituted hydrazine derivative in a solvent such as ethanol or2-propanol provided a route to 4,5-dihydropyridazinone of generalstructure B. Keto-acid intermediates with substitution at the 4- and5-position are known and may be readily prepared. Pyridazinones withR^(3/4a) and R^(5/5a) fused with heteroaryl or cycloalkyl groups aresynthesized from the corresponding anhydrides or acid-esters. In caseswhere R¹ is a protecting group, deprotection gives R¹═H compounds ofgeneral structure C. Standard transformations of NH III by alkylation orreductive amination reactions produce examples of general structure D.The 4,5-dihydropyridazinones structure D may be oxidized to an aromaticpyridazinone of general structure E using MnO₂, CuCl₂, DDQ, seleniumoxide, DMSO/base or sodium 3-nitrobenzenesulfonate in the presence ofsodium hydroxide. NH(R⁸═H) pyridazinones may be alkylated with alkyl orsubstituted alkyl groups using an R⁸-halide, a base, for example K₂CO₃,Cs₂CO₃ or NaH, in an inert solvent such as DMF, THF or CH₃CN. Exampleswherein R⁸ is H may be converted to analogs wherein R⁸ is aryl orheteroaryl by standard palladium or copper coupling reactions using theappropriate aryl or heteroaryl halide.

Aryl pyridazinone examples of the invention may also be synthesizedusing standard Suzuki cross-coupling chemistry. A spiro boron etherderivatives of general structure F, is subjected to a palladiumcatalyzed cross-coupling reaction (Suzuki reaction) with a pyridazinederivative of general structure G or a pyridazinone of structure Hwherein the R^(4a), R^(5a) or R⁷ group may be a halogen, preferably Bror Ito produce examples of general structure J and K.

Spiro-pyrrolidine, -azepine and -3-piperidine examples of the inventionmay be synthesized using methods outlined in for the spiro-4-piperidineexamples starting with N-Boc-3-pyrrolidinone,N-Boc-hexahydro-1H-azepin-4-one or N-Boc-3-piperidone, respectively, inplace of N-Boc-4-piperidone.

EXAMPLES

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments as shown below.These examples are given for illustration of the invention and are notintended to be limiting thereof.

Example 16-(1-Cyclobutyl-spiro[benzofuran-2(3H),4′-piperidine]-5-yl)-4,5-dihydro-2H-pyridazin-3-one

Step 1: Synthesis of1′-Trifluoroacetyl-spiro[benzofuran-2(3H)-4′-piperidine]

A solution of spiro[benzofuran-2(3H)-4′-piperidine] (8 g, 40 mmol) inmethylene chloride (70 mL) was treated with pyridine (8 mL, 100 mmol)and trifluoroacetic anhydride (7 mL, 50 mmol) at 10° C. The mixture wasstirred at 10° C. for 2 h, then quenched with 1N HCl and extracted twicewith methylene chloride. The combined organic layer was dried (Na₂SO₄),filtered, and concentrated to produce1′-trifluoroacetyl-spiro[benzofuran-2(3H)-4′-piperidine] (10.86 g, 91%),

MS m/z=286 (M+H).

Step 2: Synthesis of 1′-Trifluoroacetyl-5-(4-oxo-butyric acid ethylester)-spiro[benzofuran-2(3H), 4′-piperidine]

A mixture of the product from step 1 (0.51 g, 1.8 mmol) and ethylsuccinyl chloride (0.25 mL, 1.8 mmol) in methylene chloride (2 mL) wascooled to 0° C. Tin tetrachloride (1M solution in methylene chloride)(2.32 mL, 2.32 mmol) was added at 10° C., stirred for 30 min thenquenched with aqueous 2N HCl at 0° C. The aqueous layer was extractedtwice with methylene chloride and the combined organic layer was washedwith brine, dried (Na₂SO₄), filtered, and concentrated. The product waspurified by ISCO silica gel chromatography (40 g column) using 20% EtOAcin hexane to furnish 1′-trifluoroacetyl-5-(4-oxo-butyric acid ethylester)-spiro[benzofuran-2(3H), 4′-piperidine] (0.61 g, 83%), MS m/z=414(M+H).

Step 3: Synthesis of 6-(Spiro[benzofuran-2(3H),4′-piperidine]-5-yl)-4,5-dihydro-2H-pyridazin-3-one

A mixture of the product from step 2 (0.61 g, 1.5 mmol) and hydrazinemonohydrate (0.57 mL, 11 mmol) in isopropanol (7 mL) was heated at 110°C. for 15 h. Isopropanol was evaporated at reduced pressure andpartitioned between saturated aqueous sodium bicarbonate solution andmethylene chloride. The aqueous layer was extracted twice with methylenechloride and the combined organics was washed with brine, dried(Na₂SO₄), filtered, and concentrated to provide6-(spiro[benzofuran-2(3H),4′-piperidine]-5-yl)-4,5-dihydro-2H-pyridazin-3-one (0.4 g, 95%), MSm/z=286 (M+H). The crude material was used for the next reaction withoutfurther purification.

Step 4: Synthesis of 6-(1-Cyclobutyl-spiro[benzofuran-2(3H),4′-piperidine]-5-yl)-4,5-dihydro-2H-pyridazin-3-one

A solution of the product from step 3 (0.4 g, 1.4 mmol) in a mixture ofDMF (2 mL) and MeOH (10 mL) was stirred under argon. Cyclobutanone (0.42mL, 6.4 mmol), sodium cyanoborohydride (0.35 g, 5.6 mmol) and aceticacid (0.2 mL, 3.17 mmol) were added sequentially and stirred at 60° C.for 15 h. The reaction mixture was concentrated at reduced pressure andpartitioned between aqueous 1M sodium carbonate solution and methylenechloride. The aqueous layer was extracted twice with methylene chlorideand the combined organics was washed with brine, dried (Na₂SO₄),filtered, and concentrated to provide a crude product. The crude productwas purified by ISCO (40 g column) chromatography using 5 to 10%methanol in methylene chloride to 10% methanol containing 4 mL ammoniumhydroxide in methylene chloride. The recovered pure product wasdissolved in methylene chloride and washed with saturated aqueous sodiumbicarbonate solution, brine, dried (Na₂SO₄), filtered, and concentrated.The product was crystallized from a mixture of methylene chloride,ethanol, ether, and hexane to give example 1(6-(1-cyclobutyl-spiro[benzofuran-2(3H),4′-piperidine]-5-yl)-4,5-dihydro-2H-pyridazin-3-one) (94 mg, 20%, 96%purity), mp 207-209° C. (methylene chloride, ethanol, ether, andhexane), MS m/z=340 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 1.57-2.15 (m,12H), 2.37-2.56 (m, 2H), 2.60 (t, J=16.16 Hz, 2H), 2.76-2.87 (m, 1H),2.96 (t, J=16.32 Hz, 2H), 3.01 (S, 2H), 6.78 (d, J=8.33 Hz, 1H), 7.46(d, J=8.36 Hz, 1H), 7.59 (S, 1H), 8.44 (S, 1H).

Example 2

This compound was prepared using the method described for Example 1using cyclopropane dicarboxylic acid anhydride to givel′-cyclobutyl-5-(3,4-diaza-bicyclo[4.1.0]hepten-2-one-5-yl)-spiro[benzofuran-2(3H),4′-piperidine]:mp 189-191° C., MS m/z=352 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 0.97 (dt,J1=10.14 Hz, J2=5.31 Hz, 1H), 1.54-2.13 (m, 12H), 2.17-2.24 (m, 1H),2.40-2.58 (m, 4H), 2.77-2.89 (m, 1H), 3.03 (s, 2H), 6.81 (d, J=8.42 Hz,1H), 7.57 (d, J=8.50 Hz, 1H), 7.63 (s, 1H), 8.23 (s, 1H).

Example 36-(1-Cyclobutyl-spiro[benzofuran-2(3H),4′-piperidine]-5-yl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one

Step 1: Synthesis of1′-Trifluoroacetyl-5-(propanoyl)-spiro[benzofuran-2(3H), 4′-piperidine]

A mixture of 1′-trifluoroacetyl-spiro[benzofuran-2(3H)-4′-piperidine](3.1 g, 11 mmol) and propanoyl chloride (1 mL, 10 mmol) in methylenechloride (25 mL) was cooled at 10° C. Tin tetrachloride (1M solution inmethylene chloride) (14.14 mL, 14.11 mmol) was added at 10° C. andstirred at 10° C. for 30 min then quenched with aqueous 2N HCl at 0° C.The aqueous layer was extracted twice with methylene chloride and thecombined organics was washed with brine, dried (Na₂SO₄), filtered, andconcentrated to provide a crude product. The crude product was purifiedby ISCO (120 g) chromatography using 22% EtOAc in hexane to produce1′-trifluoroacetyl-5-(propanoyl)-spiro[benzofuran-2(3H)-4′-piperidine](2.2 g, 59%), MS m/z=342 (M+H).

Step 2: Synthesis of 1′-Trifluoroacetyl-5-(3-methyl-4-oxo-butyric acidethyl ester)-spiro[benzofuran-2(3H), 4′-piperidine]

A solution of 1′-trifluoroacetyl-5-(propanoyl)-spiro[benzofuran-2(3H),4′-piperidine] (2.2 g, 6.45 mmol) in tetrahydrofuran (22 mL) was cooledat 0° C. Lithium diisopropylamide, (2M solution in THF) (3.56 mL, 7.09mmol) was added dropwise and warmed to rt for 30 min. The reaction wascooled to 0° C. and ethyl bromoacetate (0.79 mL, 7.1 mmol) was addeddropwise and warmed to rt for 30 min then quenched with aqueous 1M HClacid at 0° C. The aqueous layer was extracted twice with methylenechloride and the combined organics was washed with brine, dried(Na₂SO₄), filtered, and concentrated to give a crude1′-trifluoroacetyl-5-(3-methyl-4-oxo-butyric acid ethylester)-spiro[benzofuran-2(3H), 4′-piperidine] (3.34 g), MS m/z=428(M-55).

Step 3: Synthesis of 6-(Spiro[benzofuran-2(3H),4′-piperidine]-5-yl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one

A mixture of 1′-trifluoroacetyl-5-(3-methyl-4-oxo-butyric acid ethylester)-spiro[benzofuran-2(3H), 4′-piperidine] (3.34 g, 7.8 mmol) andhydrazine monohydrate (3 mL, 60 mmol) in isopropanol (25 mL) was heatedat 110° C. for 15 h. Isopropanol was evaporated at reduced pressure andpartitioned between saturated aqueous sodium bicarbonate solution andmethylene chloride. The aqueous layer was extracted twice with methylenechloride and the combined organics was washed with brine, dried(Na₂SO₄), filtered, and concentrated to produce a crude6-(spiro[benzofuran-2(3H),4′-piperidine]-5-yl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one(1.4 g, 60%), MS m/z=300 (M+H). The crude material was used for the nextreaction without further purification.

Step 4: Synthesis of 6-(1-Cyclobutyl-spiro[benzofuran-2(3H),4′-piperidine]-5-yl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one

A solution of the product from step 3 (6-(spiro[benzofuran-2(3H),4′-piperidine]-5-yl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one) (1.4 g,4.7 mmol) in a mixture of DMF (2 mL) and MeOH (10 mL) was stirred underargon. Cyclobutanone (1.4 mL, 19 mmol), sodium cyanoborohydride (1.2 g,19 mmol) and acetic acid (0.65 mL, 11.36 mmol) were added sequentiallyand stirred at 60° C. for 13 h. The reaction mixture was concentrated atreduced pressure and partitioned between aqueous 1M sodium carbonatesolution and methylene chloride. The aqueous layer was extracted twicewith methylene chloride and the combined organics was washed with brine,dried (Na₂SO₄), filtered, and concentrated to provide a crude product.The crude product was purified by ISCO (120 g column) chromatographyusing 5 to 10% methanol in methylene chloride to obtain a pure product.The pure product was crystallized from a mixture of methylene chloride,ethanol, ether, and hexane to produce6-(1-cyclobutyl-spiro[benzofuran-2(3H),4′-piperidine]-5-yl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one(512 mg, 31%, 98% purity), mp 213-215° C. (methylene chloride, ethanol,ether, and hexane), MS m/z=354 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 1.25(d, J=7.35 Hz, 3H), 1.63-2.14 (m, 10H), 2.36-2.57 (m, 4H), 2.70 (dd,J1=16.90 Hz, J2=6.78 Hz, 1H), 2.76-2.86 (m, 1H), 3.01 (s, 2H), 3.27-3.37(m, 1H), 6.785 (d, J=8.43 Hz, 1H), 7.50 (d, J=8.47 Hz, 1H), 7.63 (s,1H), 8.61 (s, 1H).

Example 46-(Cyclobutyl-spiro[benzofuran-2(3H),4′-piperidine]-5-yl)-5-methyl-2H-pyridazin-3-one

A mixture of6-(1-cyclobutyl-spiro[benzofuran-2(3H),4′-piperidine]-5-yl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one(202 mg, 0.57 mmol) and cesium carbonate (372 mg, 1.14 mmol) in dimethylsulfoxide (8.5 mL) was heated at 130° C. 4 h. The mixture was cooled toRT and partitioned between water and methylene chloride. Sodium chloridewas added to the mixture and the aqueous layer was extracted twice withmethylene chloride. The combined organics was washed with brine, dried(Na₂SO₄), filtered, and concentrated to provide a crude product. Thecrude product was purified by ISCO (80 g) chromatography using 5% to 10%methanol in methylene chloride to 10% methanol containing 1% ammoniumhydroxide in methylene chloride. The recovered product was dissolved inmethylene chloride and washed with saturated aqueous sodium bicarbonatesolution, brine, dried (Na₂SO₄), filtered, and concentrated to produce apure product. The pure product was crystallized from a mixture ofmethylene chloride, methanol, ether and hexane to give example 4(6-(cyclobutyl-spiro[benzofuran-2(3H),4′-piperidine]-5-yl)-5-methyl-2H-pyridazin-3-one)(42 mg, 21%, 96% purity), mp 243-245° C., MS m/z=352 (M+H); ¹H NMR (400MHz, CDCl₃): δ 1.55-2.97 (m, 18H), 3.05 (s, 2H), 6.80-6.86 (m, 2H),7.14-7.19 (m, 1H), 7.21 (s, 1H), 10.55 (s, 1H).

Example 51′-Cyclobutyl-[6-[4,5-dihydro-2H-pyridazin-3-one-6-yl)-spiro[3,4-dihydro-benzopyran-2,4′-piperidine]

Step 1: Synthesis of1′-Trifluoroacetyl-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

A solution of 3,4-dihydrospiro[benzopyran-2,4′-piperidine].HCl (7 g, 30mmol) in methylene chloride (60 mL) was treated with pyridine (10 mL,100 mmol) and trifluoroacetic anhydride (4.5 mL, 32 mmol) at 10° C. Themixture was stirred at 10° C. for 3 h then quenched with 1N HCl andextracted twice with methylene chloride. The combined organics was dried(Na₂SO₄), filtered, and concentrated to produce a crude product. Thecrude product was purified by ISCO (330 g column) chromatography using12 to 18% ethyl acetate in hexane to obtain a pure1′-trifluoroacetyl-3,4-dihydrospiro[benzopyran-2,4′-piperidine] (7.48 g,72%), MS m/z=300 (M+H).

Step 2: Synthesis of 1′-Trifluoroacetyl-6-(4-oxo-butyricacid)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

A mixture of1′-trifluoroacetyl-spiro[3,4-dihydrobenzopyran-2,4′-piperidine] (0.66 g,2.20 mmol) and succinic anhydride (0.24 g, 2.43 mmol) in1,2-dichloroethane (8 mL) was cooled to 0° C. Aluminium chloride (0.90g, 7 mmol) was added at 0° C. and the mixture was heated at 80° C. for16 h then quenched with aqueous 1N HCl at 0° C. The aqueous layer wasextracted twice with methylene chloride and the combined organics waswashed with brine, dried (Na₂SO₄), filtered, and concentrated to providea crude 1′-trifluoroacetyl-6-(4-oxo-butyricacid)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine] (0.97 g), MS m/z=400(M+H) and 399 (M−H).

Step 3: Synthesis of6-(4,5-Dihydro-2H-pyridazin-3-one-6-yl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

A mixture of 1′-trifluoroacetyl-6-(4-oxo-butyricacid)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine] (0.97 g, 2.4 mmol)and hydrazine monohydrate (2.5 mL, 80 mmol) in isopropanol (12 mL) washeated at 110° C. for 19 h. Isopropanol was evaporated at reducedpressure and azeotrophed three times with benzene to produce a crude6-(4,5-dihydro-2H-pyridazin-3-one-6-yl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine](0.92 g), MS m/z=300 (M+H). The crude product was used for the nextreaction without further purification.

Step 4:1′-Cyclobutyl-6-(4,5-dihydro-2H-pyridazin-3-one-6-yl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

A solution of the product from step 3 (0.92 g, 3.10 mmol) in a mixtureof DMF (2 mL) and MeOH (6 mL) was stirred under argon. Cyclobutanone(0.9 mL, 10 mmol), sodium cyanoborohydride (0.8 g, 10 mmol) and aceticacid (0.42 mL, 7.4 mmol) were added sequentially and stirred at 60° C.for 20 h. The reaction mixture was concentrated at reduced pressure andpartitioned between aqueous 1M sodium carbonate solution and methylenechloride. The aqueous layer was extracted twice with methylene chlorideand the combined organics was washed with brine, dried (Na₂SO₄),filtered, and concentrated to provide a crude product. The crude productwas purified by ISCO (40 g column) chromatography using 4.5 to 10%methanol in methylene chloride to 10% methanol containing 4 mL ofammonium hydroxide in methylene chloride obtain a pure product. Therecovered product was dissolved in methylene chloride and washed withsaturated sodium sodium bicarbonate solution, brine, dried (Na₂SO₄),filtered, and concentrated. The pure product was crystallized from amixture of methylene chloride, ethanol, ether, and hexane to produce1′-cyclobutyl-6-(4,5-dihydro-2H-pyridazin-3-one-6-yl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine](39 mg, 95% purity), mp 242-243.5° C. (methylene chloride, ethanol,ether, and hexane), MS m/z=354 (M+H); ¹H NMR (400 MHz, CDCl₃): δ1.52-2.02 (m, 12H), 2.03-2.14 (m, 2H), 2.19-2.36 (m, 2H), 2.59 (t,J=8.49 Hz, 2H), 2.64-2.75 (m, 1H), 2.79-2.91 (m, 2H), 2.96 (t, J=7.82Hz, 2H), 6.85-6.90 (m, 1H), 7.45-7.50 (m, 2H), 8.43 (s, 1H).

The following examples were prepared using the methods disclosed herein.

Example 66-(3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one-5-yl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

Example 6: mp 284-287° C.; MS m/z=312 (M+H); ¹H NMR (400 MHz, DMSO): δ0.71 (dt, J1=9.28 Hz, J2=4.71 Hz, 1H), 1.63-1.90 (m, 6H), 1.90-2.09 (m,1H), 2.56-2.64 (m, 1H), 2.75-2.84 (m, 2H), 2.92-3.02 (m, 4H), 6.82-6.90(m, 2H), 7.52-7.59 (m, 2H), 10.69 (s, 1H).

Example 71′-Cyclobutyl-6-(3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one-5-yl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

Example 7: mp 228-230° C.; MS m/z=366 (M+H); ¹H NMR (400 MHz, CDCl₃): δ0.96 (dt, J1=9.75 Hz, J2=4.76 Hz, 1H), 1.57-2.15 (m, 14H), 2.17-2.35 (m,3H), 2.50-2.58 (m, 1H), 2.79-2.91 (m, 2H), 6.87-6.92 (m, 2H), 7.51-7.58(m, 2H), 8.29 (s, 1H).

Example 81′-Cyclopentyl-6-(3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one-5-yl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

Example 8: mp 229-231° C.; MS m/z=380 (M+H); ¹H NMR (400 MHz, CDCl₃): δ0.96 (dt, J1=9.74 Hz, J2=4.83 Hz, 1H), 1.41-1.99 (m, 16H), 2.18-2.25 (m,1H), 2.41-2.70 (m, 4H), 2.77-2.91 (m, 3H), 6.88-6.93 (m, 1H), 7.51-7.58(m, 2H), 8.32 (s, 1H).

Example 91′-Isopropyl-[6-(3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one-5-yl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

Example 9: mp 160.6-164° C. (methylene chloride, ethanol, ether, andhexane); MS m/z=354 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 0.96 (dt, J1=10.14Hz, J2=5.21 Hz, 1H), 1.10-1.22 (m, 6H), 1.74-1.95 (m, 7H), 2.17-2.26 (m,1H), 2.50-2.92 (m, 8H), 6.88-6.93 (m, 1H), 7.51-7.59 (m, 2H), 8.31 (s,1H).

Example 101′-Cyclobutyl-6-(3,4-diaza-bicyclo[4.2.0]oct-4-en-2-one-5-yl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

Example 10: mp 202-204° C. (methylene chloride, ethanol, ether, andhexane); MS m/z=380 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 1.54-2.93 (m,23H), 3.32-3.42 (m, 1H), 3.83-3.93 (m, 1H), 6.81-6.87 (m, 1H), 7.32-7.40(m, 2H), 8.34 (s, 2H).

Example 111′-Cyclobutyl-6-(4,4-dimethyl-4,5-dihydro-2H-pyridazin-3-one-6-yl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

Example 11: mp 246-248° C. (methylene chloride, ethanol, ether, andhexane); MS m/z=382 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 1.25 (s, 6H),1.62-1.93 (m, 8H), 1.95-2.16 (m, 4H), 2.24-2.39 (m, 1H), 2.65-2.95 (m,7H), 6.83-6.90 (m, 2H), 7.43-7.52 (m, 2H), 8.44 (s, 1H).

Example 121′-Cyclobutyl-6-(5-methyl-4,5-dihydro-2H-pyridazin-3-one-6-yl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

Step 1: Synthesis of1′-Trifluoroacetyl-6-(propanoyl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

A mixture of1′-trifluoroacetyl-spiro[3,4-dihydrobenzopyran-2,4′-piperidine] (1.49 g,4.98 mmol) and propanoyl chloride (0.4 mL, 5 mmol) in methylene chloride(13 mL) was cooled at 10° C. Tin tetrachloride (1M solution in methylenechloride) (0.76 mL, 6.5 mmol) was added at 10° C. and stirred at 10° C.for 20 min then quenched with aqueous 2N HCl at 0° C. The aqueous layerwas extracted twice with methylene chloride and the combined organicswas washed with brine, dried (Na₂SO₄), filtered, and concentrated toprovide a crude product. The crude product was purified by ISCO (80 gcolumn) chromatography using 17 to 35% EtOAc in hexane to produce1′-trifluoroacetyl-6-(propanoyl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine](1.42 g, 81%),

MS m/z=356 (M+H).

Step 2: Synthesis of 1′-Trifluoroacetyl-6-(3-methyl-4-oxo-butyric acidethyl ester)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

A solution of the product from step 1(1′-trifluoroacetyl-6-(propanoyl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine])(1.4 g, 3.9 mmol) in tetrahydrofuran (13 mL) was cooled at 0° C. Lithiumdiisopropylamide, (2M solution in THF) (2.16 mL, 4.33 mmol) was addeddropwise and warmed to rt for 30 min. The reaction was cooled again to0° C. and ethyl bromoacetate (0.48 mL, 4.30 mmol) was added dropwise andwarmed to RT for 30 min then quenched with aqueous 1M HCl acid at 0° C.The aqueous layer was extracted twice with methylene chloride and thecombined organics was washed with brine, dried (Na₂SO₄), filtered, andconcentrated to give a crude1′-trifluoroacetyl-6-(3-methyl-4-oxo-butyric acid ethylester)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine] (2.21 g), MS m/z=442(M+H).

Step 3: Synthesis of6-(5-methyl-4,5-dihydro-2H-pyridazin-3-one-6-yl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

A mixture of the product from step 2 (2.21 g, 5.01 mmol) and hydrazinemonohydrate (1.5 mL, 30 mmol) in isopropanol (15 mL) was heated at 110°C. for 36 h. Isopropanol was evaporated at reduced pressure andazeotrophed twice with benzene to produce a crude product (2.45 g), MSm/z=314 (M+H). The material was used for the next reaction withoutfurther purification.

Step 4: Synthesis of1-Cyclobutyl-6-(5-methyl-4,5-dihydro-2H-pyridazin-3-one-6-yl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

A solution of the product from step 3 (2.45 g, 7.82 mmol) in a mixtureof DMF (5 mL) and MeOH (15 mL) was stirred under argon. Cyclobutanone(1.8 mL, 24 mmol), sodium cyanoborohydride (1.2 g, 19 mmol) and aceticacid (0.90 mL, 20 mmol) were added sequentially and stirred at 60° C.for 24 h. The reaction mixture was concentrated at reduced pressure andpartitioned between aqueous 1M sodium carbonate solution and methylenechloride. The aqueous layer was extracted twice with methylene chlorideand the combined organics was washed with brine, dried (Na₂SO₄),filtered, and concentrated to provide a crude product. The crude productwas purified by ISCO (40 g) chromatography using 2 to 10% methanol inmethylene chloride to 10% methanol containing 4 mL of ammonium hydroxidein methylene chloride to obtain a pure product. The recovered pureproduct was dissolved in methylene chloride and washed with saturatedsodium sodium bicarbonate solution, brine, dried (Na₂SO₄), filtered, andconcentrated. The pure product was crystallized from a mixture ofmethylene chloride, ethanol, ether, and hexane to produce1-cyclobutyl-6-(5-methyl-4,5-dihydro-2H-pyridazin-3-one-6-yl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]:(550 mg, 19%, 95% purity), mp 207-209° C. (methylene chloride, ethanol,ether, and hexane), MS m/z=368 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 1.26(d, J=7.33 Hz, 3H), 1.61-2.01 (m, 12H), 2.02-2.14 (m, 2H), 2.19-2.32 (m,2H), 2.42-2.50 (m, 1H), 2.60-2.74 (m, 2H), 2.77-2.90 (m, 2H), 3.28-3.39(m, 1H), 6.84-6.92 (m, 1H), 7.47-7.54 (m, 2H), 8.50 (s, 1H).

Example 131′-Cyclobutyl-6-(5-methyl-2H-pyridazin-3-one-6-yl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

A mixture of example 12 (103 mg, 0.28 mmol) and cesium carbonate (536mg, 1.60 mmol) in dimethyl sulfoxide (6 mL) was heated at 100-110° C.for 27 h. The mixture was cooled to rt and partitioned between water andmethylene chloride. Sodium chloride was added to the mixture and theaqueous layer was extracted three times with methylene chloride. Thecombined organics was washed with brine, dried (Na₂SO₄), filtered, andconcentrated to provide a crude product. The crude product was purifiedby ISCO (40 g column) chromatography using 5% to 10% methanol inmethylene chloride to 10% methanol containing 4% ammonium hydroxide inmethylene chloride. The recovered product was dissolved in methylenechloride and washed with saturated aqueous sodium bicarbonate solution,brine, dried (Na₂SO₄), filtered, and concentrated to produce a pureproduct. The pure product was crystallized from a mixture of methylenechloride, ethanol, ether and hexane to give1′-cyclobutyl-6-(5-methyl-2H-pyridazin-3-one-6-yl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine](32 mg, 21%, 93% purity), mp 270-272° C. (methylene chloride, ethanol,ether and hexane), MS m/z=366 (M+H); 1H NMR (400 MHz, DMSO-d₆): δ1.56-1.85 (m, 11H), 1.92-2.03 (m, 2H), 2.12 (s, 3H), 2.14-2.26 (m, 1H),2.45-2.55 (m, 2H), 2.72-2.80 (m, 3H), 6.76-6.82 (m, 2H), 7.15-7.19 (m,2H), 12.92 (s, 1H).

Example 14

1′-Isopropyl-[6-(4,4-dimethyl-4,5-dihydro-2H-pyridazin-3-one-6-yl)-spiro[3,4-dihydro[benzopyran-2,4′-piperidine]:mp 210-213° C. (methylene chloride, ethanol, ether, and hexane); MSm/z=370 (M+H); ¹H NMR (400 MHz, CDCl₃): δ 1.15 (d, 6H, J=6.5 Hz), 1.25(s, 6H), 1.8-1.91 (m, 6H), 2.66-2.84 (m, 9H), 6.88 (d, 2H, J=8.1 Hz),7.47-7.49 (m, 2H), 8.45 (s, 1H).

Step 1

To a solution of 5-bromo-spiro[benzofuran-2-(3H)-4′-piperidine] (260.0mg, 0.97 mmol) in methanol (5.0 mL, 120 mmol) was added 100 μl (1.75mmol) of AcOH followed by cyclobutanone (679.6 mg, 9.7 mmol) at rt. Tothis mixture was added sodium cyanoborohydride (200 mg, 3.18 mmol) insmall portions over 5 min. After 5 min. HPLC indicated about 10% ofstarting material. Added another 100 μl of AcOH followed by another 200mg of NaCNBH₃. After stirring for 15 min, LCMS indicated totaldisappearance of the starting material. The mixture was concentrated andextracted with CH₂Cl₂/sat. NaHCO₃. After evaporation and drying(Na₂SO₄), a pale yellow oil was obtained which was purified by ISCOchromatography using CH₂Cl₂ and 0-10% MeOH containing 1% aq. NH₄OH toafford the title compound as a waxy white solid (250 mg, 74%). Mp 79-80°C., MS: m/z 322/324 (M+1, Br isotopic peaks). ¹HNMR (400 MHz, CDCl₃): δ7.28 (d, J=0.75 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H),2.98 (s, 2H), 2.80 (m, 1H), 2.1-2.6 (br.s, 4H) & 1.6-2.1 (m, 10H).

Example 151′-Cyclobutyl-5-(6-chloropyridazin-3-yl)spiro[benzofuran-2(3H)-4′-piperidine]

Into a dry, round bottom flask was addedtris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.024 mmol) andtricyclohexylphosphine (28.0 mg, 0.1 mmol) under N₂ atmosphere. Dioxane(6 mL) was added and the dark solution was stirred for 30 min at rt. Tothis dark brownish solution was added4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (0.20 g,0.79 mmol), potassium acetate (0.10 g, 1.02 mmol) and a solution of1′-cyclobutyl-5-bromo-spiro[benzofuran-2(3H)-4′-piperidine] (245.00 mg,0.76 mmol) in dioxane (5 mL) in that order. The mixture was purged withN₂ for 10 min. and heated at 80° C. After refluxing for 14 h, the LCMSindicated the absence of the bromide with the expected m/z 370 mass forthe borolane. The crude borolane intermediate was subjected to theSuzuki coupling reaction by adding 3,6-dichloropyridazine (0.55 g, 3.69mmole), (Ph₃P)₄Pd (85 mg, 0.073 mmole), THF (15 mL), EtOH (5 mL) andsaturated aqueous NaHCO₃ (8 mL). After 10 h, HPLC indicated the expectedproduct as the major peak. The reaction was concentrated and purified byISCO chromatography (DCM/MeOH/NH₄OH) to obtain the product a beige solid(80 mg, 28%). mp 193-194° C., MS: m/z 356 (M+1). ¹HNMR (CDCl₃): δ 7.97(s, 1H), 7.73-7.77 (m, 2H), 7.52 (dd, J=8.8, 1.5 Hz, 1H), 6.9 (d, J=8.4Hz, 1H), 3.1 (s, 2H), (2.8, m, 1H), 2.4-2.6 (br.s, 4H) & 1.65-2.15 (m,10H).

Example 16 1′-Cyclobutyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)spiro[benzofuran-2(3H)-4′-piperidine]

To example 15(1′-cyclobutyl-5-(6-chloropyridazin-3-yl)spiro[benzofuran-2(3H)-4′-piperidine])(75.00 mg, 0.2108 mmol) in acetic acid (5.0 mL, 88 mmol) was addedsodium acetate (100.00 mg, 1.219 mmol) and refluxed for 3 h. The mixturewas evaporated, the residue co-evaporated with toluene (2×10 mL) andthen chromatographed by ISCO chromatography (DCM/MeOH/NH₄OH) to affordthe title compound 50 mg (68%). mp 227-228° C., MS: m/z 338 (M+1). ¹HNMR(CDCl₃): δ 12 (s, 1H), 7.7 (d, J=9.85 Hz, 1H), 7.6 (s, 1H), 7.55 (d,J=8.4 Hz, 1H), 7.05 (d, J=9.85 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 3.05 (s,2H), (2.85, m, 1H), 2.4-2.6 (br.s, 4H) & 1.65-2.15 (m, 10H).

Example 176-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]-6-yloxy)-4-chloropyridazine

Step 1

1′-t-Butyloxycarbonyl-4-oxo-6-hydroxy-spiro[3Hbenzopyran-2,4′-piperidine]

A solution of 2,5-dihydroxyacetophenone (15 g, 98 mmol),4-oxo-piperidine-1-carboxylic acid tert-butyl ester (20 g, 100 mmol) andpyrrolidine (21 mL, 260 mmol) in methanol (146 mL) was stirred at refluxfor 23 h and concentrated under vacuum to produce a red oily crudematerial. The oily crude material was purified by ISCO (330 g column)chromatography using 27 to 80% ethyl acetate in hexane to afford theproduct of step 1 (27 g, 82%), mp 72-74° C. (ethyl acetate, ether andhexane), MS m/z=332 (M−H).

Step 2

1′-t-Butyloxycarbonyl-4,6-dihydroxy-spiro[3Hbenzopyran-2,4′-piperidine]

A solution of the product from step 1 (4.51 g, 13.5 mmol) in methanol(50 mL) was cooled to 15° C. and sodium borohydride was added slowly andthe mixture was further stirred for 30 min and then concentrated. Thecrude residue was partitioned between methylene chloride and water andthe aqueous layer was extracted twice with methylene chloride. Thecombined organics was washed with brine, dried (Na₂SO₄), filtered andconcentrated to produce the product of step 2 (4.1 g, 90%), mp 171-173°C. (ethyl acetate, ether and hexane), MS m/z=334 (M−H).

Step 3

6-hydroxy-spiro[3Hbenzopyran-2,4′-piperidine]

A solution of the product from step 2 (23.5 g, 70.1 mmol) andtriethylsilane (49 mL, 310 mmol) in methylene chloride (150 mL) wascooled to 10° C. Trifluoroacetic acid (78 mL, 1000 mmol) was addeddropwise and further stirred at room temperature for 15 h. The mixturewas concentrated under vacuum and then azeotroped thrice with toluene toproduce amber color oily material, which upon standing under vacuum gavea solid product. The crude product was triturated with a mixture ofhexane:ether (1:1 ratio, 175 mL) to produce a pure product, which wasdried at 80° C. to give a tan solid as the TFA salt (21 g, 90%), mp208-210° C. (ether and hexane), MS m/z=220 (M+H).

Step 4

1′-cyclobutyl-4-hydroxy-spiro[3,4-dihydro-benzopyran-2,4′-piperidine]

A solution of the product from step 3 (0.76 g, 3.5 mmol) in a mixture ofDMF (2 mL) and MeOH (10 mL) was stirred under argon. Cyclobutanone (1.00mL, 10 mmol), acetic acid (0.4 mL, 7 mmol) sodium cyanoborohydride (0.9g, 10 mmol) were added sequentially and stirred at 60° C. for 15 h. Thereaction mixture was concentrated at reduced pressure and partitionedbetween aqueous 1M sodium carbonate solution and methylene chloride. Theaqueous layer was extracted twice with methylene chloride and thecombined organics was washed with brine, dried (Na₂SO₄), filtered, andconcentrated to provide a crude product. The recovered pure product wasdissolved in methylene chloride and washed with saturated aqueous sodiumbicarbonate solution, brine, dried (Na₂SO₄), filtered, and concentrated.The product was crystallized from a mixture of methylene chloride,ethanol, ether, and hexane to produce the product of step 4 (0.5 g,53%), mp 211-213° C. (methylene chloride, ethanol, ether and hexane), MSm/z=274 (M+H).

Step 5 Example 17

A solution of the product from step 4 (200 mg, 0.73 mmol) in dimethylsulfoxide (10 mL) was added sodium hydride (35 mg, 1.4 mmol) at roomtemperature. After stirring for 30 min at room temperature 3,6-dichloropyridazine (218 mg, 1.46 mmol) was added and the reaction mixture washeated to 60° C. for 1 h and poured into brine solution at roomtemperature. The aqueous layer was extracted four times with methylenechloride and the combined organics was washed with brine, dried(Na₂SO₄), filtered and concentrated to produce a crude material. Thecrude material was purified by ISCO (40 g) chromatography using amixture of methanol in methylene chloride to afford Example 17 (250 mg,87%), mp 128-130° C. (methylene chloride, methanol, ether and hexane),MS m/z=386 (M+H).

Example 186-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]-6-yloxy)-2H-pyridazin-3-one

A mixture of example 17 (209 mg, 0.54 mmol) and sodium acetate (32 mg,0.39 mmol) in acetic acid (5 mL) was heated to 110-115° C. for 7 h. Thereaction mixture was concentrated and azeotroped twice with toluene thenpartitioned between methylene chloride and the aqueous saturated sodiumbicarbonate solution. The aqueous layer was extracted twice withmethylene chloride and the combined organics was washed with brine,dried (Na₂SO₄), filtered, and concentrated to afford relatively pureproduct. The pure product was crystallized from a mixture of methylenechloride, methanol, ether, and hexane to produce 6-(3,4-dihydrospiro[2H-1-benzopyran-2,4′-piperidine]-6-yloxy)-2H-pyridazin-3-one as anoff-white solid (170 mg, 76%), mp 233-235° C. (methylene chloride,methanol, ether and hexane), MS m/z=368 (M+H); ¹H NMR (400 MHz, CDCl₃):δ 1.54-2.01 (m, 10H), 2.03-2.13 (m, 2H), 2.18-2.32 (m, 2H), 2.60-2.71(m, 2H), 2.74-2.89 (m, 3H), 6.82-6.91 (m, 3H), 7.00 (d, J=9.92 Hz, 1H)7.185 (d, J=9.91 Hz, 1H), 9.84 (br s, 1H).

Example 191′-Cyclobutyl-[6-(2H-pyridazin-3-one-5-yl)-spiro[3,4-dihydro-benzopyran-2,4′-piperidine]

To a 100 mL flask was added 2-hydroxymethyl-5-iodo-2H-pyridazin-3-one(0.19 g, 0.76 mmol),1′-cyclobutyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)-spiro[3,4-dihydro-benzopyran-2,4′-piperidine](0.34 g, 0.89 mmol), tetrakis(triphenylphosphine)palladium(0) (0.088 g0.076 mmol), K₂CO₃ (0.53 g, 3.8 (mmol), in 1,2-dimethoxyethane (8 mL)and water (8 mL). The reaction mixture was flashed with N₂ for 25 minand was then heated to reflux for 16 h. The reaction was cooled to rtand small amount of NaCNBH₃ was added and stirred for 5 min. Thereaction was diluted with CH₂Cl₂/MeOH (100 mL, 3:1) then washed withsaturated NaHCO₃, brine and dried (Na₂SO₄). The product was purified byprep TLC (6% MeOH/CH₂Cl₂) and the product collected and triturated withCH₃CN to give 115 mg; mp 216-219° C.; 1HNMR (DMSO): 12.95 (s, 1H), 8.25(s, 1H), 7.6 (s, 1H), 7.45 (d, 1H), 6.95 (s, 1H), 6.8 (d, 1H), 2.8 (m,3H), 2.2-2.3 (br, 2H), 1.95-2.0 (br, 2H), 1.6-1.9 (m, 11H). MS m/z 352(M+1)

The following examples were synthesized using the methods for example 19with 6-chloro-2-methyl-2H-pyridazin-3-one (Ex. 20) and3-chloro-6-methoxypyridazine (Ex. 21).

Example Structure Mp (° C.) MS m/z 20

147-149 366 (M + H) 21

273-275 352 (M + H)

Racemic Example 10 was separated into two isomers using chiralchromatography; ChiralCel OJ-H and 0.1% diethylamine in 35%methanol/CO₂. The individual isomers are designated as Example 22 (PeakA, elutes first from chiral column) and Example 23 (Peak B, elutessecond from chiral column).

Example Structure mp (° C.) MS m/z 22

>300 HCl 380 (M + H) 23

>300 HCl 380 (M + H)

Example 241′-Cyclobutyl-6-(3-(2-pyridazin-3-one)propyloxy]-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

1′-Cyclobutyl-4-hydroxy-spiro[3,4-dihydro-benzopyran-2,4′-piperidine](0.3 g, 1.1 mmol) in DMF (7 mL) was added NaH (88 mg, 3.7 mmol). After0.5 h, 2-(3-chloropropyl)-2-H-pyridazin-3-one (0.2 g, 1.15 mmol) wasadded and the reaction heated to 60° C. for 1 h, concentrated andpartitioned between DCM and aqueous NaHCO₃, NaCl solution and dried(Na₂SO₄). The product was purified by silica gel chromatography (5-12%MeOH/DCM) to give 360 mg (80%). mp 207-209° C. (HCl salt), MS m/z=410(M+H).

Example 251′-Cyclobutyl-6-(3-(2-pyridazin-3-one)-2-hydroxypropyloxy]-spiro[3,4-dihydrobenzopyran-2,4′-piperidine]

This compound was synthesized using the method for example 24 and2-oxiranylmethyl-2H-pyridazin-3one. mp 201-203° C. (HCl salt), MSm/z=426 (M+H).

The following examples were synthesized from6-bromo-1′-cyclobutyl-spiro[1,3-benzodioxine-2,4′-piperidine] usingmethods for example 19-21.

Example Structure Mp (° C.) MS m/z 26

258-262 (HCl) 354 (M + 1) 27

185-187 368 (M + H) 28

273-275 354 (M + H) 29

230-232 368 (M + H) 30

369-270 (HCl) 382 (M + H) 31

255-257 (HCl) 368 (M + H) 32

258-259 404 (M + H) 33

260-262 430 (M + H)

Synthesis of6-bromo-1′-cyclobutyl-spiro[1,3-benzodioxine-2,4′-piperidine]

To a solution of 6-bromo-1′H-spiro[1,3benzodioxine-2,4′-piperidine] (238g, 0.84 mol) and cyclobutanone (117 g, 1.676 mol) in THF (2 L) on an icebath was added NaBH(OAc)₃ (266 g, 1.255 mol) portion wise over 25 minunder nitrogen. The resulting mixture was allowed to warm to rt andstirred overnight. The reaction mixture was poured into a mixture of ice(1.7 L), saturated NaHCO₃ (1.7 L) and ethyl acetate (1.7 L) withvigorous stirring. After separation, the aqueous phase was adjusted topH 11 by addition of 2M NaOH and extracted with ethyl acetate (2 L×2).The extracts were combined, washed with saturated NaHCO₃ (1.5 L), brine(1.5 L), dried over Na₂SO₄ and concentrated. The obtained solid waspurified by column chromatography (hexanes/ethyl acetate 3/1 to 1/1) togive 208 g (73%). MS m/z=339 (M+1).

Example 341′-Cyclobutyl-6-[5H-4,4-dimethylpyridazin-3-one)-spiro[1,3-benzodioxine-2,4′-piperidine]

Example 34

Method A: Into a 3-neck round bottom flask6-bromo-1′-cyclobutyl-spiro[1,3benzodioxine-2,4′-piperidine] (5.0 g, 15mmol) in 80 mL THF/ether (4:1) was cooled at −76° C. under an atmosphereof nitrogen sec-Butyl lithium (1.4 M in cyclohexane, 13 mL, 18 mmol) wasadded dropwise and the mixture stirred at that temperature for 4 h.Then, 3,3-dimethyl-dihydrofuran-2,5-dione (2.8 g, 22 mmol) in THF (10mL) was added dropwise, the cooling bath was removed and the reactionwas allowed to warm to 0° C. for 1 h. LCMS showed the acid product (MSm/z=386 (M−1). Water (5 mL) was added, and the mixture concentrated andthe resulting oil dissolved in iPrOH (40 mL). Hydrazine hydrate (2 mL,50 mmol) was added and the reaction heated at 110° C. for 24 h, cooledto rt and concentrated to remove iPrOH. The water layer was decantedfrom the white semi-solid material, which was dissolved in DMC and dried(MgSO₄). The product was purified on ISCO (silica gel, 95/5 increasingto 9/1 DCM/MeOH) to give 1.9 g (33%). mp 266-269° C. (HCl salt;MeOH-ether), ¹H NMR (DMSO) δ 11.4 (s, 1H), 10.8 (s, 1H), 7.6-7.65 (m,1H), 7.54 (s, 1H), 6.9-6.95 (m, 1H), 4.92-4.94 (d, 2H, J=10 Hz),3.68-3.76 (p, 1H, J=7.6 Hz), 3.2-3.3 (b, 3H), 2.88 (m, 2H), 2.78 (m,2H), 2.37-2.4 (m, 1H), 2.16-2.25 (m, 6H), 1.67-1.77 (m, 2H), 1.06 (s,6H). LCMS m/z=384 (M+1).

Method B:

Example 34

Step 1. To 1′-carboxylic acid tert-butylester-6-bromo-spiro[1,3-benzodioxine-2,4′-piperidine] (14.58 g, 37.94mmol) in ether (300 mL) under argon at −78° C. was addedsec-butyllithium (1.4 M; 32.5 mL, 45.5 mmol) dropwise and the reactionwas stirred at −78° C. for 30 min. 3,3-Dimethyldihydrofuran-2,5-dione inether (10 mL) was added and the reaction was stirred for 30 min at −78°C. and quenched with water (˜40 mL). The reaction was warmed to rt andconcentrated to remove the organic solvents. The aqueous layer wasacidified with 5N HCl to pH=3-4, extracted with dichloromethane (150mL), and the organic layer was washed with water and brine, dried oversodium sulfate, and concentrated. The product was purified using silicagel column chromatography (2-3% methanol/dichloromethane). The fractionswere concentrated, triturated with dichloromethane (˜5 mL)/ether (˜10mL)/hexanes (˜15-20 mL), and filtered off white solid to obtain 5.52 g(34%); MS m/z: 434 (M+H).

Step 2. To the product from step 1 (5.52 g, 12.7 mmol) (1′-carboylicacid tert-butyl ester-6-(2,2-dimethyl-4-oxo-butyricacid)-spiro[1,3-benzodioxine-2,4′-piperidine]) in isopropyl alcohol (70mL) was added hydrazine monohydrate (0.956 mL, 19.1 mmol) and thereaction was heated at 80° C. overnight and concentrated. The residuewas partitioned between water/dichloromethane, washed with brine, driedover sodium sulfate, and concentrated to obtain 5.4 g (>95%) of a crudeproduct; MS m/z: 430 (M+H).

Step 3. Example 35. To the product from step 2 (1′-carboxylic acidtert-butylester-6-(4,4-dimethyl-4,5-dihydro-2H-pyridazin-2-one)-spiro[1,3-benzodioxine-2,4′-piperidine](5.46 g, 12.7 mmol) in dichloromethane (100 mL) was addedtrifluoroacetic acid (10 mL, 129.8 mmol) and the reaction was stirredfor 4 h at rt and concentrated. The product was azeotroped with benzeneand dried under vacuum to give 5.6 g of crude product as an oil; MS m/z:330 (M+H).

Step 4. Example 34. To the product from step 3(1′-H-6-(4,4-dimethyl-pyridazinone)-spiro[1,3-benzodioxine-2,4′-piperidine]trifluoroaceticacid salt) (5.6 g, 12.6 mmol) and cyclobutanone (2.83 mL, 37.9 mmol) inDMF (10 mL)/methanol (50 mL)/acetic acid (3 mL) under argon cooled at 0°C. was added sodium cyanoborohydride (3.97 g, 63.2 mmol) slowly inportions. The reaction was heated at 60° C. overnight and concentrated.The reaction was partitioned between dichloromethane/1N sodiumcarbonate, washed with water and brine, dried over sodium sulfate, andconcentrated. The product was purified using a single step silica gelcolumn (5% methanol/dichloromethane) and concentrated. The free base wasdissolved in chloroform (˜50 mL) and 1N HCl/ether (˜17 mL) was added.The product was collected after addition of ether to give 3.64 g (67%)of white solid; mp 269-270° C. MS m/z: 384 (M+H).

The following examples were synthesized using modifications to theprocedure for example 34 or methods described herein.

Example Structure Mp (° C.) MS m/z 36

192-194 356 (M + H) 37

>300 (HCl) 368 (M + H) 38

271-274 (HCl) 382 (M + H) 39

209-214 (HCl) 370 (M + H) 40

265-267 (HCl) 368 (M + H) 41

>300 (HCl) 382 (M + H)

Utility

The compounds of the present invention are useful, inter alia, astherapeutic agents. Particularly, the compounds are useful forinteracting with the H₃ receptor. In one embodiment, the presentinvention provides a method for treating or preventing diseases anddisorders, such as those disclosed herein, which comprises administeringto a subject in need of such treatment or prevention a therapeuticallyeffective amount of a compound of the present invention.

In an additional embodiment, the present invention provides a method forinhibiting H₃ activity comprising providing a compound of the presentinvention in an amount sufficient to result in effective inhibition.Particularly, the compounds of the present invention can be administeredto treat such diseases and disorders such as narcolepsy or othersleep/wake disorders, such as obstructive sleep apnea/hypopnea syndrome,and shift work sleep disorder; feeding behavior disorder, eatingdisorders, obesity, cognition disorders, arousal disorders, memorydisorders, mood disorders, mood attention alteration, attention deficithyperactivity disorder (ADHD), Alzheimer's disease/dementia,schizophrenia, pain, stress, migraine, motion sickness, depression,psychiatric disorders, epilepsy, gastrointestinal disorders, respiratorydisorders (such as asthma), inflammation, and myocardial infarction. Incertain embodiments, the compounds can be administered to treatnarcolepsy or other sleep/wake disorders, such as obstructive sleepapnea/hypopnea syndrome, and shift work sleep disorder; obesity,cognition disorders, attention deficit hyperactivity disorder (ADHD),and dementia. In other embodiments, the compounds can be administered totreat narcolepsy or other sleep/wake disorders, such as obstructivesleep apnea/hypopnea syndrome, and shift work sleep disorder; or theycan used to treat obesity, or they can used to treat cognitiondisorders, or they can used to treat attention deficit hyperactivitydisorder (ADHD), or they can used to treat dementia.

Compounds of the invention either have demonstrated or are expected todemonstrate inhibition of H₃ and thereby for utility for treatment ofthe indications described herein. Such utilities can be determinedusing, for example, the following assays as set forth below. They arenot intended, nor are they to be construed, as limiting the scope of thedisclosure.

Rat H₃ Assays:

Cell line development and membrane preparation. The rat H₃ receptor cDNAwas PCR amplified from reverse-transcribed RNA pooled from rat thalamus,hypothalamus, striatum and prefrontal cortex with a sequencecorresponding to by #338-1672 of Genbank file #NM_(—)053506, encodingthe entire 445-amino-acid rat histamine H₃ receptor. This was engineeredinto the pIRES-neo3 mammalian expression vector, which was stablytransfected into the CHO-A3 cell line (Euroscreen, Belgium), followed byclonal selection by limiting dilution. Cells were harvested and cellpellets were frozen (−80° C.). Cell pellets were resuspended in 5 mMTris-HCl, pH 7.5 with 5 nM EDTA and a cocktail of protease inhibitors(Complete Protease Inhibitior Tablets, Roche Diagnostics). Cells weredisrupted using a polytron cell homogenizer and the suspension wascentrifuged at 1000×g for 10 minutes at 4° C. The pellet was discardedand the supernatant centrifuged at 40,000×g for 30 min at 4° C. Thismembrane pellet was washed in membrane buffer containing 50 mM Tris-HCl,pH 7.5 with 0.6 mM EDTA, 5 mM MgCl₂ and protease inhibitors,recentrifuged as above and the final pellet resuspended in membranebuffer plus 250 mM sucrose and frozen at −80° C.

Radioligand Binding. Membranes were resuspended in 50 mM Tris HCl (pH7.4), 5 mM MgCl₂, 0.1% BSA. The membrane suspensions (10 μg protein perwell) were incubated in a 96 well microtiter plate with[³H]-N-alpha-methylhistamine (approximately 1 nM final concentration),test compounds at various concentrations (0.01 nM-30 μM) andscintillation proximity beads (Perkin Elmer, FlashBlueGPCR ScintillatingBeads) in a final volume of 80 μl for 4 hours at room temperature,protected from light. Non-specific binding was determined in thepresence of 10 μM clobenpropit. Radioligand bound to receptor, andtherefore in proximity to the scintillation beads, was measured using aMicroBeta scintillation counter.

GTPγS Binding. Membranes were resuspended in 20 mM HEPES pH 7.4containing 1 mM EDTA, 0.17 mg/ml dithiothreitol, 100 mM NaCl, 30 μg/mlsaponin and 5 mM MgCl₂. For measurement of inverse agonist activity,increasing concentrations of test compounds were incubated in a 96 wellmicrotiter plate with 10 μg/well membrane protein, 5 μM GDP,scintillation proximity beads (Perkin Elmer, FlashBlueGPCR ScintillatingBeads) and [³⁵S]-GTPγS (0.1 nM final concentration). Followingincubation for 45 minutes in the dark at room temperature, themicrotiter plate was centrifuged at 1000×g for 5 minutes andradioactivity bound to the membranes was counted using a MicroBetascintillation counter. Non-specific binding was measured in the presenceof 10 μM GTP. A decrease in bound [³⁵S]-GTPγS is indicative of H₃receptor inverse agonist activity in this assay. Antagonist activity oftest compounds was determined in a similar experiment under thefollowing conditions. Membranes were resuspended in 20 mM HEPES pH 7.4containing 1 mM EDTA, 0.17 mg/ml dithiothreitol, 200 mM NaCl, 30 μg/mlsaponin and 20 mM MgCl₂. The membranes were incubated at 10 μg/wellmembrane protein in a microtiter plate with increasing concentrations oftest compounds, 20 μM GDP, scintillation proximity beads and [³⁵S]-GTPγS(0.1 nM final concentration) plus 30 nM R-alpha-methylhistamine. Themicrotiter plates were incubated and processed as described above. Adecrease in R-alpha-methylhistamine stimulated [³⁵S]-GTPγS binding isindicative of H₃ receptor antagonist activity in this assay.

Human H₃ Assays:

Methods: CHO cells stably expressing the human H₃ receptor (GenBank:NM_(—)007232) were harvested and cell pellets were frozen (−80° C.).Cell pellets were resuspended in 5 mM Tris-HCl, pH 7.5 with 5 nM EDTAand a cocktail of protease inhibitors (Complete Protease InhibitiorTablets, Roche Diagnostics). Cells were disrupted using a polytron cellhomogenizer and the suspension was centrifuged at 1000×g for 10 minutesat 4° C. The pellet was discarded and the supernatant centrifuged at40,000×g for 30 min at 4° C. This membrane pellet was washed in membranebuffer containing 50 mM Tris-HCl, pH 7.5 with 0.6 mM EDTA, 5 mM MgCl₂and protease inhibitors, recentrifuged as above and the final pelletresuspended in membrane buffer plus 250 mM sucrose and frozen at −80° C.

Radioligand Binding. Membranes were resuspended in 50 mM Tris HCl (pH7.4), 5 mM MgCl₂, 0.1% BSA. The membrane suspensions (10 μg protein perwell) were incubated in a 96 well microtiter plate with[³H]-N-alpha-methylhistamine (approximately 1 nM final concentration),test compounds at various concentrations (0.01 nM-30 μM) andscintillation proximity beads (Perkin Elmer, FlashBlueGPCR ScintillatingBeads) in a final volume of 80 μl for 4 hours at room temperature,protected from light. Non-specific binding was determined in thepresence of 10 μM clobenpropit. Radioligand bound to receptor, andtherefore in proximity to the scintillation beads, was measured using aMicroBeta scintillation counter.

GTPγS Binding. Membranes were resuspended in 20 mM HEPES pH 7.4containing 1 mM EDTA, 0.17 mg/ml dithiothreitol, 100 mM NaCl, 30 μg/mlsaponin and 5 mM MgCl₂. For measurement of inverse agonist activity,increasing concentrations of test compounds were incubated in a 96 wellmicrotiter plate with 10 μg/well membrane protein, 5 μM GDP,scintillation proximity beads (Perkin Elmer, FlashBlueGPCR ScintillatingBeads) and [³⁵S]-GTPγS (0.1 nM final concentration). Followingincubation for 45 minutes in the dark at room temperature, themicrotiter plate was centrifuged at 1000×g for 5 minutes andradioactivity bound to the membranes was counted using a MicroBetascintillation counter. Non-specific binding was measured in the presenceof 10 μM GTP. A decrease in bound [³⁵S]-GTPγS is indicative of H₃receptor inverse agonist activity in this assay. Antagonist activity oftest compounds was determined in a similar experiment under thefollowing conditions. Membranes were resuspended in 20 mM HEPES pH 7.4containing 1 mM EDTA, 0.17 mg/ml dithiothreitol, 200 mM NaCl, 30 μg/mlsaponin and 20 mM MgCl₂. The membranes were incubated at 10 μg/wellmembrane protein in a microtiter plate with increasing concentrations oftest compounds, 20 μM GDP, scintillation proximity beads and [³⁵S]-GTPγS(0.1 nM final concentration) plus 30 nM R-alpha-methylhistamine. Themicrotiter plates were incubated and processed as described above. Adecrease in R-alpha-methylhistamine stimulated [³⁵S]-GTPγS binding isindicative of H₃ receptor antagonist activity in this assay.

Other assays that may be used in connection with the present inventionare set forth below. Examples of the present invention can be tested inthe following in vivo models:

Evaluation of Wake Promoting Activity in Rats

The methodology utilized for evaluating wake promoting activity of testcompounds is based on that described by Edgar and Seidel, Journal ofPharmacology and Experimental Therapeutics, 283:757-769, 1997, andincorporated herein in its entirety by reference. Compounds of theinvention either have demonstrated or are expected to demonstrateutility for wake promoting activity.

Dipsogenia Model: Inhibition of histamine agonist-induced water drinkingin the rat. Histamine, and the H₃-selective agonist(R)-α-methylhistamine (RAMH) induce water drinking behavior in the ratwhen administered either peripherally or centrally (Kraly, F. S., June,K. R. 1982 Physiol. Behav. 28: 841; Leibowitz, S. F. 1973 Brain Res.63:440; Ligneau X., Lin, J-S., Vanni-Mercier G., Jouvet M., Muir J. L.,Ganellin C. R., Stark H., Elz S., Schunack W., Schwartz, J-C. 1998 JPharmcol. Exp. Ther. 287:658-66; Clapham, J. and Kilpatrick G. J. 1993Eur. 1 Pharmacol. 232:99-103) an effect which is blocked by H₃ receptorantagonists thioperamide and ciproxifan. Compounds of the inventioneither have demonstrated or are expected to block RAMH induce waterdrinking behavior.

Novel object discrimination: Novel object discrimination (NOD; alsoreferred to as novel object recognition) is an assay for short-termvisual recognition memory that was first described by Ennaceur andDelacour (Ennaceur, A. and Delacour, J. (1988) Behav Brain Res 31:47-59).

Social recognition: Social recognition (SR) is an assay for short-termsocial (olfactory) memory that was first described by Thor and Holloway(1982). Thor, D. and Holloway, W. (1982) J Comp Physiolog Psychcol 96:1000-1006.

Compounds of the invention either have demonstrated or are expected todemonstrate inhibition of H₃ and thereby utility for treatment of theindications described herein.

Table B lists the Human and Rat H₃ binding data for Examples 1-18 of thepresent invention. Binding constants (K_(i)) for Examples 1-41 in theHuman H₃ and Rat H₃ methods described herein are expressed by letterdescriptor to indicate the following ranges: “+++” is less than 200 nM;“++” is 200-1000 nM; “+” is >1000 nM.

TABLE B Human H₃ Rat H₃ Example Structure Ki nM Ki nM 1

+++ +++ 2

+++ +++ 3

+++ ++ 4

+++ +++ 5

+++ +++ 6

+ + 7

+++ +++ 8

+++ +++ 9

+++ +++ 10

+++ +++ 11

+++ +++ 12

+++ +++ 13

+++ +++ 14

+++ +++ 15

+++ +++ 16

+++ +++ 18

+++ +++ 19

+++ +++ 20

+++ +++ 21

+++ +++ 22

+++ +++ 23

+++ +++ 24

+++ +++ 25

+++ +++ 26

+++ +++ 27

+++ +++ 28

+++ +++ 29

++ ++ 30

+++ +++ 31

+++ +++ 32

+++ +++ 33

+++ +++ 34

+++ +++ 36

+++ +++ 37

+++ +++ 38

+++ +++ 39

+++ +++ 40

+++ +++ 41

+++ +++

Dosage and Formulation

For therapeutic purposes, the compounds of the present invention can beadministered by any means that results in the contact of the activeagent with the agent's site of action in the body of the subject. Thecompounds may be administered by any conventional means available foruse in conjunction with pharmaceuticals, either as individualtherapeutic agents or in combination with other therapeutic agents, suchas, for example, analgesics. The compounds of the present invention arepreferably administered in therapeutically effective amounts for thetreatment of the diseases and disorders described herein to a subject inneed thereof.

A therapeutically effective amount can be readily determined by theattending diagnostician, as one skilled in the art, by the use ofconventional techniques. The effective dose will vary depending upon anumber of factors, including the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected, theformulation of the active agent with appropriate excipients, and theroute of administration. Typically, the compounds are administered atlower dosage levels, with a gradual increase until the desired effect isachieved.

Typical dose ranges are from about 0.01 mg/kg to about 100 mg/kg of bodyweight per day, with a preferred dose from about 0.01 mg/kg to 10 mg/kgof body weight per day. A preferred daily dose for adult humans includesabout 25, 50, 100 and 200 mg, and an equivalent dose in a human child.The compounds may be administered in one or more unit dose forms. Theunit dose ranges from about 1 to about 500 mg administered one to fourtimes a day, preferably from about 10 mg to about 300 mg, two times aday. In an alternate method of describing an effective dose, an oralunit dose is one that is necessary to achieve a blood serum level ofabout 0.05 to 20 μg/ml in a subject, and preferably about 1 to 20 μg/ml.

The compounds of the present invention may be formulated intopharmaceutical compositions by admixture with one or morepharmaceutically acceptable excipients. The excipients are selected onthe basis of the chosen route of administration and standardpharmaceutical practice, as described, for example, in Remington: TheScience and Practice of Pharmacy, 20^(th) ed.; Gennaro, A. R., Ed.;Lippincott Williams & Wilkins: Philadelphia, Pa., 2000. The compositionsmay be formulated to control and/or delay the release of the activeagent(s), as in fast-dissolve, modified-release, or sustained-releaseformulations. Such controlled-release, or extended-release compositionsmay utilize, for example biocompatible, biodegradable lactide polymers,lactide/glycolide copolymers, polyoxyethylene-polyoxypropylenecopolymers, or other solid or semisolid polymeric matrices known in theart.

The compositions can be prepared for administration by oral means;parenteral means, including intravenous, intramuscular, and subcutaneousroutes; topical or transdermal means; transmucosal means, includingrectal, vaginal, sublingual and buccal routes; ophthalmic means; orinhalation means. Preferably the compositions are prepared for oraladministration, particularly in the form of tablets, capsules or syrups;for parenteral administration, particularly in the form of liquidsolutions, suspensions or emulsions; for intranasal administration,particularly in the form of powders, nasal drops, or aerosols; or fortopical administration, such as creams, ointments, solutions,suspensions aerosols, powders and the like.

For oral administration, the tablets, pills, powders, capsules, trochesand the like can contain one or more of the following: diluents orfillers such as starch, or cellulose; binders such as microcrystallinecellulose, gelatins, or polyvinylpyrrolidones; disintegrants such asstarch or cellulose derivatives; lubricants such as talc or magnesiumstearate; glidants such as colloidal silicon dioxide; sweetening agentssuch as sucrose or saccharin; or flavoring agents such as peppermint orcherry flavoring. Capsules may contain any of the afore listedexcipients, and may additionally contain a semi-solid or liquid carrier,such as a polyethylene glycol. The solid oral dosage forms may havecoatings of sugar, shellac, or enteric agents. Liquid preparations maybe in the form of aqueous or oily suspensions, solutions, emulsions,syrups, elixirs, etc., or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assurfactants, suspending agents, emulsifying agents, diluents, sweeteningand flavoring agents, dyes and preservatives.

The compositions may also be administered parenterally. Thepharmaceutical forms acceptable for injectable use include, for example,sterile aqueous solutions, or suspensions. Aqueous carriers includemixtures of alcohols and water, buffered media, and the like. Nonaqueoussolvents include alcohols and glycols, such as ethanol, and polyethyleneglycols; oils, such as vegetable oils; fatty acids and fatty acidesters, and the like. Other components can be added includingsurfactants; such as hydroxypropylcellulose; isotonic agents, such assodium chloride; fluid and nutrient replenishers; electrolytereplenishers; agents which control the release of the active compounds,such as aluminum monostearate, and various co-polymers; antibacterialagents, such as chlorobutanol, or phenol; buffers, and the like. Theparenteral preparations can be enclosed in ampules, disposable syringesor multiple dose vials. Other potentially useful parenteral deliverysystems for the active compounds include ethylene-vinyl acetatecopolymer particles, osmotic pumps, implantable infusion systems, andliposomes.

Other possible modes of administration include formulations forinhalation, which include such means as dry powder, aerosol, or drops.They may be aqueous solutions containing, for example,polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oilysolutions for administration in the form of nasal drops, or as a gel tobe applied intranasally. Formulations for topical use are in the form ofan ointment, cream, or gel. Typically these forms include a carrier,such as petrolatum, lanolin, stearyl alcohol, polyethylene glycols, ortheir combinations, and either an emulsifying agent, such as sodiumlauryl sulfate, or a gelling agent, such as tragacanth. Formulationssuitable for transdermal administration can be presented as discretepatches, as in a reservoir or microreservoir system, adhesivediffusion-controlled system or a matrix dispersion-type system.Formulations for buccal administration include, for example lozenges orpastilles and may also include a flavored base, such as sucrose oracacia, and other excipients such as glycocholate. Formulations suitablefor rectal administration are preferably presented as unit-dosesuppositories, with a solid based carrier, such as cocoa butter, and mayinclude a salicylate.

As those skilled in the art will appreciate, numerous modifications andvariations of the present invention are possible in light of the aboveteachings. It is therefore understood that within the scope of theappended claims, the invention may be practiced otherwise than asspecifically described herein, and the scope of the invention isintended to encompass all such variations.

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1. A compound of Formula (I):

or a stereoisomeric form, mixture of stereoisomeric forms, or apharmaceutically acceptable salt thereof, wherein: R¹ is H, C₁-C₄ alkyl,or C₃-C₈ cycloalkyl; W is —CH₂—, —CH₂CH₂—, or —CH₂—O—; k is 0, 1, or 2;m is 0, 1, or 2; and the sum of m and k is 1, 2, or 3; Y²═Y³ is—C(X)═CH— or —CH═C(X)—; X is R², —OR², —(C₁-C₃ alkyl)-R², —O—(C₁-C₃alkyl)-R², —NHR², —NHC(═O)R², or —NHC(═O)NHR²; wherein said C₁-C₃ alkylis optionally substituted with —OH or C₁-C₄ alkoxy; R² is

A is F, Cl, or Br; R³ is H, F, or C₁-C₄ alkyl; R⁴ is H, F, or C₁-C₄alkyl; R^(4A) is H, F, Cl, Br, or C₁-C₄ alkyl; R⁵ is H, F, or C₁-C₄alkyl; R^(5A) is H, F, Cl, Br, C₁-C₄ alkyl or phenyl; or, R⁴ and R⁵,together with the carbon atoms to which they are attached, form a fusedC₃-C₆ cycloalkyl ring optionally substituted with 1, 2, or 3 R¹⁴; or,R^(4A) and R^(5A), together with the carbon atoms to which they areattached, form a fused phenyl ring optionally substituted with 1, 2, or3 R¹⁴; a C₃-C₆ cycloalkyl ring optionally substituted with 1, 2 or 3R¹⁴; a 5 to 6 membered fused heteroaryl ring system containing one, two,or three heteroatoms selected from N, O, and S, wherein said heteroarylring system is optionally substituted with 1, 2, or 3 R¹⁴; or a 5 to 6membered fused heterocycloalkyl ring system containing one, two, orthree heteroatoms selected from N, O, S, SO, and SO₂, wherein saidheterocycloalkyl ring system is optionally substituted with 1, 2, or 3R¹⁴; R⁶ is H, F, or C₁-C₄ alkyl; R⁷ is H, F, Cl, Br, or C₁-C₄ alkyl; R⁸is H, —C(═O)R²⁷, —CO₂R²⁷, C₁-C₆ alkyl optionally substituted by 1-3 R²⁰;C₃-C₈ cycloalkyl optionally substituted by 1-3 R^(20A); C₆-C₁₀ aryloptionally substituted by 1-3 R^(20A); C₇-C₁₅ arylalkyl optionallysubstituted by 1-3 R^(20A); or a 5 to 10 membered heteroaryl ring systemcontaining one, two, or three heteroatoms selected from N, O, and S,wherein said heteroaryl ring system is optionally substituted with 1-3R^(20A); R⁹, at each occurrence, is independently F, Cl, Br, C₁-C₄alkyl, or C₁-C₄ alkoxy; R¹⁰ is F, Cl, Br, C₁-C₃ alkyl, or C₁-C₃ alkoxy;R¹⁴ at each occurrence is independently F, Cl, Br, I, —OR²¹, —OR²²,—NR²³R²⁴, —NHOH, —NO₂, —CN, —CF₃, (═O), —C(═O)R²¹, —CO₂R²¹,—OC(═O)NR²³R²⁴, —NR²⁷C(═S)R²¹, —SR²¹, —NR²⁷C(═O)R²¹, —NR²⁷C(═O)OR²¹,—OC(═O)NR²³R²⁴, —NR²⁷C(═S)R²¹, —SR²¹, —S(O)R²¹, or —S(O)₂R²¹; C₁-C₆alkyl optionally substituted with OR²⁶; C₂-C₆ alkenyl, or C₂-C₆ alkynyl;R²⁰ at each occurrence is independently F, Cl, Br, I, —OR²¹, —OR²²,—NR²³R²⁴, —NHOH, —NO₂, —CN, —CF₃, (═O), —C(═O)R²¹, —C(═O)NR²³R²⁴,—NR²⁷C(═O)R²¹, —NR²⁷C(═O)OR²¹, —OC(═O)NR²³R²⁴, —NR²⁷C(═S)R²¹, —SR²¹,—S(O)R²¹, or —S(O)₂R²¹; C₁-C₆ alkyl optionally substituted with OR²⁶;C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, phenyl, 3- to 7-memberedheterocycloalkyl group, or 5- or 6-membered heteroaryl group; R^(20A) ateach occurrence is independently F, Cl, Br, I, —OR²¹, —OR²², —NR²³R²⁴,—NHOH, —NO₂, —CN, —CF₃, (═O), —C(═O)R²¹, —CO₂R²¹, —OC(═O)R²¹,—C(═O)NR²³R²⁴, —NR²⁷C(═O)R²¹, —NR²⁷C(═O)OR²¹, —OC(═O)NR²³R²⁴,—NR²⁷C(═S)R²¹, —SR²¹, —S(O)R²¹, or —S(O)₂R²¹; C₁-C₆ alkyl optionallysubstituted with OR²⁶; C₂-C₆ alkenyl, or C₂-C₆ alkynyl; R²¹ at eachoccurrence is independently H, C₁-C₆ alkyl, C₆-C₁₀ aryl, or C₇-C₁₅arylalkyl; R²² at each occurrence is independently the residue of anamino acid after the hydroxyl group of the carboxyl group is removed;R²³ and R²⁴ at each occurrence are independently selected from H, C₁-C₆alkyl, and C₆-C₁₀ aryl; or, R²³ and R²⁴, together with the nitrogen atomto which they are attached, form a 3 to 7 membered heterocycloalkyl ringsystem containing one, two, or three heteroatoms selected from N, O, andS, wherein said heterocycloalkyl ring system is optionally substitutedwith ═O; R²⁶ is H or C₁-C₆ alkyl; R²⁷ is H or C₁-C₆ alkyl; n is 0, 1, 2,or 3; and z is 0, 1, 2, 3, 4, 5, or
 6. 2. A compound according to claim1 wherein R¹ is C₃-C₈ cycloalkyl.
 3. A compound according to claim 1wherein W is —CH₂— or —CH₂—CH₂—.
 4. A compound according to claim 1wherein R² is


5. A compound according to claim 1 wherein R⁴ and R⁵, together with thecarbon atoms to which they are attached, form a fused cyclopropyl orcyclobutyl ring.
 6. A compound according to claim 1 wherein R^(4A) andR^(5A), together with the carbon atoms to which they are attached, forma fused phenyl, thienyl, pyrrolyl, oxazolyl, pyridinyl, cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl ring.
 7. A compound according toclaim 1 wherein k is
 1. 8. A compound according to claim 1 wherein mis
 1. 9. A compound according to claim 1 wherein the sum of m and k is2.
 10. A compound according to claim 1 wherein Y²═Y³ is —C(X)═CH—.
 11. Acompound according to claim 1 wherein X is R².
 12. A compound accordingto claim 1 wherein X is —OR².
 13. A compound according to claim 1wherein R⁸ is H.
 14. A compound according to claim 1 wherein R⁸ is C₁-C₆alkyl optionally substituted by 1-3 R²⁰.
 15. A compound according toclaim 1 wherein R⁹ is C₁-C₄ alkyl.
 16. A compound according to claim 1wherein n is
 0. 17. A compound according to claim 1 wherein n is
 1. 18.A compound according to claim 1 wherein z is
 0. 19. A compound accordingto claim 1 that is a compound of Formula (II):

or a stereoisomeric form, mixture of stereoisomeric forms or apharmaceutically acceptable salt thereof, wherein: R¹ is C₃-C₈cycloalkyl; W is —CH₂— or —CH₂—CH₂—; X is R², —OR², or —NHR²; R² is

R³ is H or C₁-C₄ alkyl; R⁴ is H or C₁-C₄ alkyl; R^(4A) is H or C₁-C₄alkyl; R⁵ is H or C₁-C₄ alkyl; R^(5A) is H, C₁-C₄ alkyl, or phenyl; or,R⁴ and R⁵, together with the carbon atoms to which they are attached,form a fused C₃-C₆cycloalkyl ring optionally substituted with 1-3 R¹⁴;or, R^(4A) and R^(5A), together with the carbon atoms to which they areattached, form a fused phenyl ring optionally substituted with 1-3 R¹⁴;a C₃-C₆ cycloalkyl ring optionally substituted with 1-3 R¹⁴; a 5 to 6membered fused heteroaryl ring system containing one, two, or threeheteroatoms selected from N, O, and S, wherein said heteroaryl ringsystem is optionally substituted with 1-3 R¹⁴; or a 5 to 6 memberedfused heterocycloalkyl ring system containing one, two, or threeheteroatoms selected from N, O, S, SO, and SO₂, wherein saidheterocycloalkyl ring system is optionally substituted with 1-3 R¹⁴; R⁶is H or C₁-C₄ alkyl; and R⁷ is H or C₁-C₄ alkyl.
 20. A compoundaccording to claim 19 wherein R¹ is cyclobutyl or cyclopentyl.
 21. Acompound according to claim 19 wherein R² is


22. A compound according to claim 19 wherein R² is


23. A compound according to claim 19 wherein R⁴ and R⁵, together withthe carbon atoms to which they are attached, form a fused cyclopropyl orcyclobutyl ring.
 24. A compound according to claim 19 wherein R^(4A) andR^(5A), together with the carbon atoms to which they are attached, forma fused phenyl, thienyl, pyrrolyl, oxazolyl, pyridinyl, cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl ring.
 25. A compound according toclaim 19 wherein R⁸ is H.
 26. A compound according to claim 1 that is acompound of Formula (III):

or a stereoisomeric form, mixture of stereoisomeric forms or apharmaceutically acceptable salt thereof, wherein: R¹ is C₃-C₆cycloalkyl; W is —CH₂— or —CH₂—CH₂—; R² is

R³ is H, methyl, or ethyl; R⁴ is H, methyl, or ethyl; R^(4A) is H,methyl, or ethyl; R⁵ is H, methyl, or ethyl; R^(5A) is H, methyl, orethyl; or, R⁴ and R⁵, together with the carbon atoms to which they areattached, form a fused C₃-C₆ cycloalkyl ring; or, R^(4A) and R^(5A),together with the carbon atoms to which they are attached, form a fusedphenyl ring; C₃-C₆ cycloalkyl ring; a 5 to 6 membered fused heteroarylring system containing one, two, or three heteroatoms selected from N,O, and S; or 5 to 6 membered fused heterocycloalkyl ring systemcontaining one, two, or three heteroatoms selected from N, O, S, SO, andSO₂; R⁶ is H, methyl, or ethyl; R⁷ is H, methyl, or ethyl; R⁹, at eachoccurrence, is independently, F, Cl, methyl, ethyl, methoxy, or ethoxy;R¹⁰ is F, Cl, methyl, ethyl, methoxy, or ethoxy; and n is 0, 1, or 2.27. A compound according to claim 1 that is a compound of Formula (III):

or a stereoisomeric form, mixture of stereoisomeric forms or apharmaceutically acceptable salt thereof, wherein: R¹ is cyclobutyl orcyclopentyl; W is —CH₂— or —CH₂—CH₂—; R² is

R³ is H, methyl, or ethyl; R⁴ is H, methyl, or ethyl; R^(4A) is H,methyl, or ethyl; R⁵ is H, methyl, or ethyl; R^(5A) is H, methyl, orethyl; or, R⁴ and R⁵, together with the carbon atoms to which they areattached, form a fused cyclopropyl, cyclobutyl, or cyclopentyl ring; or,R^(4A) and R^(5A), together with the carbon atoms to which they areattached, form a fused phenyl, thienyl, pyrrolyl, oxazolyl, pyridinyl,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring; R⁶ is H,methyl, or ethyl; R⁷ is H, methyl, or ethyl; R⁹, at each occurrence, isindependently, F, Cl, methyl, ethyl, methoxy, or ethoxy; R¹⁰ is F, Cl,methyl, ethyl, methoxy, or ethoxy; and n is 0, 1, or
 2. 28. A compoundaccording to claim 1 selected from the group consisting of:

or a stereoisomeric form, mixture of stereoisomeric forms or apharmaceutically acceptable salt thereof.
 29. A pharmaceuticalcomposition comprising a compound according to claim 1, or astereoisomeric form, mixture of stereoisomeric forms or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients.
 30. A method for treating adisorder selected from the group consisting of narcolepsy or sleep/wakedisorders, feeding behavior disorders, eating disorders, obesity,cognition disorders, arousal disorders, memory disorders, mooddisorders, mood attention alteration, attention deficit hyperactivitydisorder (ADHD), Alzheimer's disease/dementia, schizophrenia, pain,stress, migraine, motion sickness, depression, psychiatric disorders,epilepsy, gastrointestinal disorders, respiratory disorders,inflammation, and myocardial infarction comprising administering to asubject in need of treatment a therapeutically effective amount of acompound according to claim 1 or a stereoisomeric form, mixture ofstereoisomeric forms or a pharmaceutically acceptable salt thereof. 31.A method according to claim 30 wherein the disorder is narcolepsy orsleep/wake disorders.
 32. A method according to claim 30 wherein thedisorder is attention deficit hyperactivity disorder.
 33. A methodaccording to claim 30 wherein the disorder is cognition disorder.